109
Bruin Research Rel;iews, 17 (1992) 109-138
0 1992 Elsevier Science Publishers B.V. All rights reserved 0165-0173/92/$05.00
BRESR 90146
Neuroendocrine regulatory mechanisms
in the choroid plexus-cerebrospinal fluid system
Christer Nilsson, Maria Lindvall-Axelsson
and Christer Owman
Department of Medical Cell Research, Section of Neurobiology, Unirersity of Lund, Lund (Sweden)
(Accepted 26 May 1992)
Key words: Choroid plexus; Cerebrospinal
fluid; Neuroendocrine; Central nervous system; Vasoactive intestinal polypeptide;
5-Hydroxytryptamine; Atrial natriuretic peptide; Vasopressin; Insulin-like growth factor; Transthyretin
CONTENTS
1. Introduction
......................................................................................
110
2. Basic features of the choroid plexus .....................................................................
2.1. Structure..
..................................................................................
2.2. Development .................................................................................
110
110
Ill
3. Functional aspects of the choroid plexus and cerebrospinal fluid .................................................
3.1. The blood-cerebrospinal
fluid barrier ...............................................................
3.2. Secretion of cerebiospinal fluid ....................................................................
3.3. Synthesis and secretion of plasma proteins ............................................................
3.4. Other functions of the choroid plexus ................................................................
3.5. Functions of the cerebrospinal fluid .................................................................
112
112
113
113
113
113
4 Neurogenic regulatory mechanisms in the choroid plexus ......................................................
4.1. Sympathetic innervation .........................................................................
4.2. Cholinergic innervation ..........................................................................
4.3. Peptidergic innervation ..........................................................................
114
114
116
116
5 Endocrine regulatory mechanisms in the choroid plexus .......................................................
5.1. 5-Hydroxytryptamine
...
.. .
........
...........................
5.2. Melatonin . . . . . .
... . .
........
...........................
5.3. Histamine
.....
.... ...
........
...........................
5.4. Atrial and brain natriuretic peptide .
........
...........................
5.5. Vasopressin
.. . ..
....
........
...........................
5.6. Angiotensin II . . . .
...
...
........
...........................
5.7. Insulin and insulin-like growth factors
........
...........................
5.8. Glucocorticoid hormones . . . .
.
........
...........................
5.9. Sex steroids and thyroid hormones . . .
........
...........................
_.a
..
5.10.1 urnermealarors.......................................................................,....,,.
118
118
119
120
120
121
122
122
123
123
124
6. The choroid plexus as source and pathway for endocrine signals targeted to the brain
6.1. Insulin-like growth factor-II
.
... ....
.. ...
... ..
6.2. Prolactin
.. .. . ...
...
...
.
..
. .
.
124
124
125
Correspondence
(46) 10 79 27.
...........................
...........................
...........................
to: C. Nilsson, Institutionen for Medicinsk Cellforskning, Lunds Universitet, Biskopsgatan 5, S-223 62 Lund, Sweden. Fax: (46)
110
6.3. Otherpeptides..................................,....
6.4. Transthyretin and the transport of thyroid hormones to the brain
7.Summary
~.........~..........~.~....~~...~~~.~.~.~~.~...~.~~~.....~.....~~~..~.........
Acknowledgements
Abbreviations
References
1.
........
. . . . . . . . . . . . . . . . . . . . . . . . . . .._..........~......I..I....I............................
... ....
175
115
.,...__.
128
I 2’)
. . . . . . . . . . ~....t............................r..................I.......................
I29
. . . . . . . . . . ..1.....__.........................t...................................~.......
129
INTRODUCX’ION
The cer~brospinal fluid (CSF) is produced by the
choroid plexuses in the four ventricles of the brain,
from where it flows to fill the subarachnoid spaces
surrounding the brain and spinal cord. Although the
CSF has an important role in the mechanical support
and chemical homeostasis of the brain@, a more dynamic function as neuroendocrine pathway for communication and integration within the brain has also been
sUggested2S”.284.3h~.
The choroid plexus appears to constitute an important part of the CSF’s role in neuroend~rine
signalling, beyond being the main site of CSF production.
Modern methodology in receptor autoradiography, in
situ hybridization and immunohistochemistry
has revealed an autonomic innervation of the choroid plexus,
but also high levels of receptors for, e.g., 5-HT, arginine vasopressin (AVP) and atria1 natriuretic peptide
(ANP) in the choroid plexus epithelium. This suggests
that centrally released transmitters released into the
CSF can act on the choroid plexus29*‘40,2S0*3373357.
While
AVP and ANP appear to be involved in choroid plexus
ion transport and CSF production48,~2~, central to their
suggested role in brain volume reguiation”9X68~‘7~7X,
the
function of 5HT in the choroid plexus is not yet
clear “(‘.
The choroid plexus also appears to constitute a
pathway for endocrine ~ommuni~tion
between the
periphery and the brain. It is the main site of synthesis
of insulin-like growth factor-II (IGF-II) in the adult
mammalian central nervous system (CNS)329. Receptors for IGF-II are present in many parts of the brain
and IGF-II has been shown to have trophic and
metabolic
effects on both glial and neuronal
cells9”~‘74~‘8’~223~235~2s’.
Especially remarkable is the synthesis and secretion of the thyroid hormone transport
protein transthyretin (‘ITR). The choroid plexus has
the body’s highest levels of this plasma protein727301.
This appears to be a phylo~eneti~a1ly old phenomenon,
apppearing before TTR synthesis occurred in the
liver13’, indicating that TTR has an important role in
thyroid hormone transport and distribution in the
brain”“. Other hormones, such as prolactin, seem to
be transported directly via specific carrier mechanisms
in the choroid plexus’~~~7~zo6~
Thus, there is increasing evidence that the choroid
plexus can act as a target, source and pathway for
neuroendocrine signalling within the brain, as summarized in Fig. 1. The present review presents the data
now available for such a role, much of which has
accumulated during the last decade.
Fig. 1. Schematic drawing of neuroendocrine signaling pathways
involving the choroid plexus-CSF system. Neurotransmitters released
within the brain parenchyma can diffuse or flow between the cells of
the ependyma (E) into the CSF and there be transported to apically
located receptors on the choroid plexus epithelium (CP) (1). The
choroid plexus might here participate as a part of a general functional response involving several parts of the brain. Two substances
that might be released in such a fashion are AVP and ANP. In the
case of 5-HT the releasing nente fibers have been identified. These
are dense, supraependymal, serotonergic nerve fiber plexuses located
in several parts of the ventricle walls. Several lines of evidence
suggest that these nerve fibers release 5-HT into the CSF from
where it reaches specific receptors in the choroid plexus epithelium
(2). Apart from acting as a target for centralfy released transmitters
(1.21, the choroid plexus also produces a growth factor (3) and
transport proteins for peripheral hormones (41. These substances
have been suggested to mediate endocrine signals to brain neurons
and glia via CSF bulk flow and diffusion within the brain parenchyma
13,4X
111
2. BASIC FEATURES OF THE CHOROID PLEXUS
2.1. Structure
The choroid plexus is present in all chordates except
Amphioxus M, but shows large species variation in size,
relative to brain size. In reptiles, birds and mammals,
the choroid plexus is located in the lateral, third and
fourth ventricles of the brain, The surface area of the
choroid plexus is increased by numerous villi, each
villus consisting of a single, cuboidal epithelium overlying a highly vascularized connective tissue stroma. The
capillaries of the choroid plexus are fenestrated while
the epithelium is sealed by tight junctions between the
epithelial cells, thus forming the blood-CSF barrier.
Fig. 2. Electron micrograph of a lateral ventricle choroid plexus from the rabbit. In A (X 1900), a one-layered cuboidal epithelium is seen
overlying a connective tissue stroma consisting of a cross-sectioned capillary, a fibroblast and collagen fibres. The epithelial cells are
characterized by numerous mitochondria and sheets of rough endoplasmic reticulum. Other prominent features are the apical microvilli forming
a brush border, the large rounded nuclei, the basolateral interdigitations and occasional tufts of cilia. The large grey structures inside the
epithelial cells are lipid droplets. In B, a high-magnification ( X 24000) electron micrograph of a part of a choroid plexus capillary is shown,
demonstrating the numerous fenestrations of the endothelial cells (arrows). The endothelial cell is situated on a basal lamina.
112
The epithelial cells are characterized by large rounded
nuclei, abundant mitochondria and rough endoplasmic
reticulum, basolateral interdigitations and numerous
microvilli protruding from the apical, luminal side (Fig.
2).
2.2. Development
The choroid plexus appears early in embryonal development, between the 6th and 8th week of gestation
in humans, arising from the neuroepithelium
surrounding
the neural tube and the underlying
mesenchyme24*,242. The central role of the epithelium
in the development of the villous choroid plexus has
been demonstrated by transplantation of epithelial cells
from the early choroid plexus anlage to the body wall,
which induces the formation of a choroid plexus-like
structure in this region36s.
During the subsequent
fetal development
the
choroid plexus of the lateral ventricles grow rapidly
and fill one-third of the lateral ventricles between
gestation weeks 9 and 17. The epithelial cells accumulate large amounts of glycogen in the cytoplasm, indicating a role for the choroid plexus in prenatal brain
growth and development J6. The choroid plexus then
gradually decreases in size relative to the whole brain
as the growth of the latter accelerates towards the later
part of the gestation.
The functional development varies depending on
the function studied. Morphometric and physiological
studies indicate that CSF secretion is very low at birth
and then increases rapidly during the first weeks postnatally2”J”‘.i72. Th is coincides with an increase in
Na+/K+-ATPase
activity and choline uptake capacity
as well’99, which parallels the ingrowth of s~pathetic
nerves1s7. These functions thus seem to be of greater
importance in postnatal life. In contrast, the synthesis
of many choroid plexus plasma proteins appear very
early in plexus development 339*340,350.
3. FUNCTIONAL
ASPECTS OF THE CHOROID PLEXUS
AND CEREBROSPINAL
FLUID
Many functions are ascribed to the choroid plexus,
which depend primarily on the epithelial cells of this
tissue56. The main functions of the choroid plexus and
the CSF are summarized below.
3.1. The blood-cerebrospinal fluid barrier
It is essential for a brain function to keep its internal chemical environment as constant as possible”. To
achieve this, the brain is separated from the blood by
the blood-brain barrier (BBB). The BBB can be divided into two parts: (1) the endothelial cells of the
brain capillaries, which separate the blood from the
extracellular fluid of the brain parenchyma and (2) the
choroid plexus epithelium and arachnoid membrane
which separate the blood from the CSF”s*hs,‘5”. For
clarity only the former will be called the BBB in the
present text, while the latter will be referred to as the
blood-CSF barrier.
While the brain capillaries are sealed by tight junctions between the endothelial ceils thus forming the
actual BBB, the capillaries in the choroid plexus are
fenestrated and permit the passage of macromolecules
into the surrounding connective tissue (Fig. 2). instead,
the epithelial cells of the choroid plexus are joined by
continuous tight junctions and thereby forms the
blood-CSF barrier. Lipophilic substances pass readily
through the respective barriers, while smaller hydrophilic substances and macromolecules are excluded
from the brain and CSF unless there is a specific
carrier for them35. In addition, a very small ‘leak’ of
the restricted substances can occur, probably through
the junctions between the brain endothelial cell$‘.
This ‘leak’ is somewhat larger for the choroid plexus
epithelium than for the BBB3’.
In addition to the choroid plexus, the arachnoid
membrane has a large contact area with the CSF,
impeding the passage of solutes from the relatively
permeable capillaries of the dura mater to the CSF”.
The CSF is in contact with the brain tissue in the
ventricles which are lined by the ependyma and in the
subarachnoid space where CSF and brain extracellular
fluid are separated by the pia mater. There are, however, no barriers between the CSF and the brain extracellular fluid and substances can pass between the
two compartments
by simple diffusion or bulk
flo~~‘@~‘~~+~s”.
The different compartments and transport routes present in the brain are shown schematically in Fig. 3.
Many substances that are necessary for proper brain
function are transported across the BBB and bloodCSF barrier by either facilitated diffusion or active
transport, e.g., glucose, amino acids, peptides, nucleotides and vitamins (cofactors)‘7.35.h5~‘58.2h”.‘22,374.
The
contribution of the CSF pathway appears to be too
small to support the total demand of the brain and the
role of the choroid plexus is probably to maintain a
CSF concentration comparable to that of the brain
extracellular fluid35,h5.This is due to the much greater
surface area of the BBB compared to the blood-CSF
barrier, traditionaily
agreed to be approximately
5000 : 135 and the longer diffusion distances from CSF
to brain compared to the distance between brain capillaries and glial cells/neurons.
However, it should be
mentioned that morphometric calculations by Keep
113
e
D
eECF
+
[C
Blood
T
CSF
Fig. 3. Schematic picture showing the four main fluid compartments
of the brain: blood, cerebrospinal fluid (CSF), extracellular fluid
(ECF) pnd the intracellular compartment (IC). Exchange of solutes
occurs between all four compartments (arrows). Selective transport
of substances occur in both directions between blood and ECF/CSF
over the BBB and blood-CSF barrier, as well as between ECF and
the IC. Direct transport between CSF and IC is also possible in
neurons that are in contact with the CSF and although quantitatively
small, this might in some cases be an important pathway for communication within the brain via the CSF. While the transport routes
described above are over barriers (BBB, blood-CSF barrier and the
plasma membranes of the cells; filled lines), there is free passage for
polar substances and macromolecules in both directions between the
ECF and CSF over the ependyma and pia mater (dashed line).
and Jones’70~‘71 suggested that the ratio may be only
2 : 1, due to the well-developed microvillous brush border of the choroid plexus epithelium. There are a few
substances (e.g., methyltetrahydrofolate,
ascorbate and
thymidine) that might enter the brain via the CSF, as
there is a high-capacity active transport system in the
choroid plexus, but no passage over the BBB322. In
summary, it appears that substances that only require
slow, long-term action, such as growth factors (IGF-II)
and transport proteins (TT’R), or are required in very
small amounts (micronutrients)322, could be transported from CSF to brain in a significant manner’59.
In addition to being physical barriers, the blood-CSF
and BBB are both enzymatic barriers in that they have
the capacity for uptake and degradation of many substances originating
either in the blood or the
brain35*65*129.
Also in this respect there are differences
between the choroid plexus and the brain endothelial
cells, for example in the concentrations of aminopeptidase M, puromycin-sensitive aminopeptidase and alkaline phosphatase, the latter two being more concentrated in the choroid plexus than in cortical microvessels316. Substances that are taken up and degraded in
this manner are, among others, serotonin, noradrenaline and their metabolites, enkephalins and other
peptides 32,33,104,196,229,341
3.2. Secretion of cerebrospinal fluid
The composition of the CSF clearly shows that it
cannot be a passively formed ultrafiltrate of plasma,
but rather a fluid modified by active secretion56*65.The
secretory morphology of the choroid plexus, the localization of Na+/K+-ATPase
to the apical part of the
choroid plexus epithelium96*311 and the analysis of
freshly secreted fluid from the choroid plexus*, strongly
suggests that the choroid plexus secretes CSF. It is now
generally agreeed that the choroid plexus is the major
source of CSF production, while the proportion of CSF
production contributed by the choroid plexus has not
been firmly established, estimates varying between 60
and 90%59765,159,274.
The main extrachoroidal source of
CSF production is probably the endothelial cells of the
brain capillaries59,65. The turnover rate of CSF is high
in mammals, around 0.5% of the total volume per min
or 4-5 times the total volume per day65.
3.3. Synthesis and secretion of plasma proteins
During recent years the synthesis of a growing number of plasma proteins has been localized to the choroid
plexus by Northern blot and in situ hybridization (for a
recent review, see ref. 300). Among these proteins are
transferrin, ceruloplasmin, cystatin C and /3,-microglobulin that appear to be synthesized both in the
choroid plexus and the brain parenchyma3,4v46T’26,
while
others such as transthyretin (TTR; prealbumin), IGF-II
and hitherto unidentified proteins seem to be synthesized exclusively in the choroid plexus epithelium and
possibly the leptomeninges but not in other parts of the
brainl26.298.300
Due to the nature of the BBB and blood-CSF
barrier, the protein content of the CSF is very low. The
reason for the high protein synthesis and secretion
from the choroid plexus246 may be to supplement the
CSF with certain important protein components. The
actual importance and role of these proteins in brain
function remain to be determined, however. TTR and
IGF-II, which could be involved in endocrine signalling
to the brain, will be further discussed below.
3.4. Other functions of the choroid plexus
The choroid plexus might have a nutritive function
in early embryological development and in those lower
vertebrates with large choroid plexuses and thin brains,
considering its large size and blood volume relative to
whole brain in these species56,60,‘37.In adult mammals
this seems unlikely due to the previously mentioned
much greater surface area of the brain capillaries compared to the choroid plexus and long diffusion distance
from CSF to much of the brain tissue, possibly with the
exception of certain micronutrients such as ascorbate322. In the lumbar spinal cord, however, the CSF is
an important nutritional pathway for spinal nerve
roots291.
114
Nathanson and Chun24” have demonstrated that the
choroid plexus can present antigen to and stimulate
proliferation of, peripheral helper T lymphocytes and
thus might play a role in immunological communication between the central nervous system (CNS) and the
periphery.
3.5. Functions of the cerebrospinal fluid
Several functions have been attributed to the CSF,
including buoyancy and protection
of the brain,
excretion of metabolites, homeostasis of the brain’s
chemical environment and as an endocrine pathway
for intracerebral
transport between different brain
areas56,65,2*4,368.
Naturally, the choroid plexus has a
large influence on CSF function, e.g., in maintaining a
constant CSF pH in the presence of large variations in
plasma pH’69*237,or for keeping a stable concentration
of ascorbate in the CSF322. As is thoroughly discussed
in this review, there is also mounting evidence that the
choroid plexus influences the composition of the CSF
in respect to certain proteins and hormones. For an
extensive review of CSF composition and function, see
ref. 65, which is the major work of reference on this
subject.
4. NEUROGENIC
THE CHOROID
REGULATORY
MECHANISMS
IN
PLEXUS
The mammalian choroid plexus contains noradrenergic sympathetic, cholinergic and peptidergic nerves,
probably of autonomic origin’“8,247. Nerve fibres from
other sources than the autonomic ganglia have not
been conclusively identified. Electron microscopy has
demonstrated nerve terminals adjacent to epithelial
and vascular elements in the choroid plexus”‘. Receptors for autonomic neurotransmitters can be found on
choroid plexus epithelial ce11s’88~249~28x.
These receptors
and their intracellular effector mechanisms are shown
in Table I and a summary of the known actions and
interactions of the different neurotransmitters
in the
choroid plexus may be found in Fig. 4.
4.1. Sympathetic innervation
The choroid plexus receives a relatively dense supply of sympathetic nerve fibres ‘86~188~192,
deriving almost
exclusively from the superior cervical ganglia”‘j. Ultrastructurally, the nerve fibres can be found in close
relation to both epithelial cells and small arterioles,
indicating a possibility for regulation of both these
TABLE I
Putative receptors demonstrated in choroid plexus epithelium
Receptors or binding sites demonstrated in choroid plexus epithelium by either receptor binding (RB), immunohistochemistry of the receptor
protein (IH), in situ hybridization of receptor mRNA (ISH), or by pharmacological characterization of the cellular, second messenger response
(PC). The cellular response is defined as the primary effector mechanism after binding of the ligand to the receptor, e.g., stimulation (+I of
cAMP production or tyrosine kinase activity. The other abbreviations are explained elsewhere in the text.
Receptor
Endogenous ligand(s)
Cellular response
Method
Refs.
;:
D,
HZ
5-HT,,
noradrenaline
noradrenaline
dopamine
histamine
S-hydroxytryptamine
+ CAMP
+ CAMP
+ CAMP
+ CAMP
PI-hydrolysis
Melatonin
Muscarinic
ANP-A
melatonin
acetylcholine
ANP, BNP
?
?
+ cGMP
Vi
AVP,_,
Ang-II
IGF-I
Insulin
AVP (and oxytocin)
AVP4-9
angiotensin II
IGF-I, IGF-II
insulin, IGF-II
200
239
2,244
55
140, 230
266,370
355
288
29,216
295
114, 271, 344,357
36
112
63, 252
22,252
Man 6-P/IGF-II
IGF-II
Growth hormone
VIP
Endothelin
Prolactin
Growth hormone
VIP
endothelin
prolactin
PI-hydrolysis
?
?
+ tyrosine kinase
+ tyrosine kinase,
transcytosis?
uptake and
degradation?
?
+ CAMP
?
transcytosis
PC
PC
RB
PC
ISH
RB
RB
RB
RB
IH
RB
RB
RB
RB
RB
GABA A
Benzodiazepine
(peripheral type)
T-2
GABA
3
RB
IH
RB
RB
RB
RB
IH
RB
252
353
179
249
175
354
228
7
3
tryptamine
?
?
RB
RB
364
268
115
structures by sympathetic nervesg7. Electrical stimulation of the superior cervical ganglia decreases CSF
production in cat and rabbit136,192 (Fig. 51, without
changing choroid plexus blood flow as measured in the
cat5, while sympathetic denervation of the choroid
plexus increases CSF production192, active transport of
choline’97 and Na+/K+-ATPase
activity198 in the rabbit.. Furthermore,
noradrenaline
has been shown to
reduce CSF production both when administered intravenously in dog and rabbit and intraventricularly in cat
and rabbit136*195,212.
The effects of noradrenaline could
be mediated by stimulation of cyclic AMP (CAMP)
formation via activation of /3-receptors200,238. The nature of the P-receptors has only been characterized
pharmacologically in functional studies and not by receptor binding. Thus, Nathanson
found that adenylate cyclase was regulated by P,-receptors in the cat,
while in vitro and in vivo studies in the rabbit indicated
a /?l-receptor-mediated
response195’200. Taken together, these findings have led to the hypothesis that
the sympathetic nervous system has a tonic inhibitory
influence on CSF production, probably by a CAMPmediated decrease of Na+/K+-ATPase
activity in the
choroid plexus epitheliumlg8.
EPITHELILH
Fig. 4. Actions and interactions of neurotransmitters in the choroid
plexus. The presence of epithelial /3 and VIP receptors, which both
mediate increases in CAMP formation in the epithelial cells, together
with VIP’s stimulatory effect on noradrenaline release, suggests that
a synergistic action exists for noradrenaline and VIP in this tissue.
Both transmitters inhibit CSF production, although this has not been
demonstrated in the same species, which lends further support to the
hypothesis of synergism. There is also evidence for the presence of
both p- and a-adrenoceptors,
as well as VIP receptors, on the
choroid plexus vasculature. For references, see text.
l
-
b
z
16
I”
Y-
c
c
5yx syx
C
Stim
Stimoff
Fig. 5. Demonstration of the regulation of CSF production in the
rabbit by sympathetic nerves. a: denervation: 1 week following sympathetic denervation (SyX) of the rabbit choroid plexus there is a
marked reduction in the noradrenaline concentration concomitant
with a highly significant increase in the rate of CSF production
compared with unoperated controls (0. Differences between mean
values ( f S.E.M.) according to the Student’s r-test: P < 0.001 in both
groups. b: stimulation: production rate of CSF before (C) and during
(Stim) bilateral electrical stimulation of the superior cervical ganglia,
which markedly reduces the rate of production (the difference, based
on paired observations, was of highest significance: P < 0.001). After
finishing stimulation (Stim off) there is a tendency to normalization
of the production rate (Stim versus Stim off: P = 0.01). Bars indicate
mean f S.E.M. Reproduced from ref. 192, with permission.
The hypothesis described above fits the results obtained in rabbit. Findings in other species are to a
certain degree contradictory, however and yields a
more complex picture. Thus, cholera toxin, which is a
very potent stimulator of CAMP formation51, stimulates
CSF production in dogs94. Saito and Wright296, in
experiments on the isolated bull-frog choroid plexus,
concluded that CAMP can increase HCO; secretion
across the choroid plexus by increasing the apical
HCO; conductance. Furthermore, sympathetic denervation of the choroid plexus in rats decreased the
uptake of choline and Na+/K+-ATPase activity, opposite to the effects in rabbit197J98. Intravenous administration of the a-adrenergic agonist phenylephrine increased CSF production in cats, possibly via stimulation of a cholinergic pathway136, although it should be
noted that the significant effects of phenylephrine was
coupled to very large increases in blood pressure.
Species differences and methodological considerations
could be responsible for the different effects that were
obtained.
CSF production decreases in dogs during experimental communicating hydrocephalus’56. In rabbits,
both CSF production and cerebral blood volume increase after sympathetic denervation, thereby increasing intracranial pressure259. Furthermore, induction of
hydrocephalus in sympathetically denervated rabbits
was not compatible with life. Electrical stimulation of
the sympathetic nerves in rabbits after kaolin-induced
acute obstructive hydrocephalus only reduced CSF
production by 19%, compared to a reduction of 32%
116
and 38% in control animals and animals with chronic
hydrocephalus, respectively ‘s9. These results were interpreted as follows: after induction of hydrocephalus
the sympathetic nerves are activated, leading to a decrease in CSF production and of cerebral blood volume
to reduce the intracranial pressure. Further stimulation
of the sympathetic nerves in this situation can only
reduce the CSF production slightly. In the chronic
animals other compensatory mechanisms have reduced
the intracranial pressure and the activity of the sympathetic nerves has diminished, making it possible to
reduce the CSF production more substantially by electrical stimulation of the sympathetic nerves259. Sympathetic regulation of choroid plexus function could
therefore have a role in the patho-physiological response to increases in intracranial pressure.
4.2. Cholinergic innervation
In contrast to the numerous investigations of the
sympathetic innervation few studies have been made of
cholinergic nerves in the choroid plexus. This is largely
due to the absence of sensitive and specific methods
for detection of cholinergic nerve fibres in peripheral
tissues. Histochemical demonstration of acetylcholinesterase has revealed presumably cholinergic nerve fibres
varying in density depending on the species studied,
the pig choroid plexus having the most well-developed
supply of positive nerve fibres”‘. The origin of these
nerve
fibres is not known’**. In addition, dense labelling of muscarinic receptors was seen in rat choroid
plexus of the lateral ventricles, but not of the third or
fourth ventricle plexuses, by receptor
autoradiography 2x8. On the other hand, biochemical determinations of choline acetyltransferase (ChAT) activity in
choroid plexus from different mammals demonstrated
little or no neuronal ChAT activity and no release of
[ “Hlacetylcholine could be detected following depolarization with either K+ or veratridine’27.
Functional studies are equally scarce. Lindvall et
a1.19” showed that the cholinergic agonist carbamylcholine inhibited CSF production in the rabbit by 20%
at a concentration of lo-” M. It was also shown that
the carbamylcholine-induced
inhibition was mediated
by muscarinic receptors and did not affect the inhibition of CSF production elicited by sympathetic nerve
stimulation. In cat, opposite results were obtained,
carbamylcholine increasing CSF production when given
intravenously, in spite of a pronounced decrease in
blood pressure. Also this effect was antagonized by
atropine 13’. Again, species differences could be involved, but no real conclusions can be made about
cholinergic function in the choroid plexus until further
studies have been made.
4.3. Peptidergic innervation
Vasoactive intestinal polypeptide (VIP) is a 28-amino
acid neuropeptide with a widespread distribution in
both the peripheral and central nervous system14’. VIP
is a well-known vasodilator in peripheral and central
arteries28,“32”352,
but has numerous other effects as well,
Fig. 6. Fluorescence
photomicrograph
of VIP-immunoreactive
nerve fibers in the lateral choroid plexus from pig. Immunoreactive
fibers
(arrowheads)
can be seen both under the epithelium (A; X 600) and perivascularly
(B; X 200). Reproduced
from ref. 247, with permission.
117
e.g., stimulation of natural killer cell activity, regulation
of cell growth and participation in ne~e-mediated
stimulation of salivary gland secretion30~92~~z1~145~*s7.
In the choroid plexus VIP-immunoreactive
nerve
fibres can be found in dense nerve plexuses around
arteries, but also in the connective tissue stroma and
(Fig. 6). VIP appears to be
close to the epithelium 194,247
present in a population of nerve fibres that also store
peptide histidine isoleucine (PHI), a peptide which
belongs to the same peptide family and is a part of the
same .precursor as VIP, and neuropeptide Y (further
described below)247. The origin(s) of the VIP-immunoreactive nerve fibres in the choroid plexus are not
known, but if the nerves enter the plexus tissue along
the arteries they might originate in the same parasympathetic ganglia that supply the cerebral vessels with
VIP fibres, namely the sphenopalatine, otic and internal carotid ganglia3%.
A single VIP-binding protein of 5.5 kDa, with binding characteristics very similar to the VIP receptors
previously described in other tissues208, has recently
been demonstrated in isolated epithelial cells from pig
choroid plexus 249(Fig. 7). This receptor might mediate
the previously described VIP-induced stimulation of
CAMP formation in cultured bovine epithelial cells and
whole rabbit choroid plexus53,200.
In vitro experiments have shown that both VIP and
PHI enhance the release of [‘Hlnoradrenaline
from
pig lateral choroid plexus during electrical stimulation248 (Fig. 8) and that VIP dilates the anterior
choroidal artery of cow ly4. To further study the function of VIP in the choroid plexus we have used an in
vivo rat model, where CSF production and choroid
plexus blood flow is measured simultaneously by the
ventriculo-cisternal
perfusion method developed by
Pappenheimer 261 and laser-doppler flowmetry25’. In
accordance with the in vitro studies, VIP increased the
blood flow in the choroid plexus by 20% at concentrations of 10-9-10-7
M when given intraventricularly
(Fig. 9) and, when infused in low doses, intravenous1~~~~.At higher intravenous doses no changes in blood
flow were seen due to the VIP-induced systemic hypotension previously described in rat and man3’~176~31s.
Ventriculo-cisternal
perfusion with VIP (10-9-10-7
M) induces a decrease in CSF production up to 30% of
control values2” (Fig. 9), indicating that choroid plexus
blood flow and CSF production are not always directly
coupled as has previously been suggested’“, although
normaI CSF production might require a certain minimum blood supply. Similar results were obtained recently by Faraci et al.99, who found that the carbonic
anhydrase inhibitor acetazolamide decreases CSF production by 55% while increasing the blood flow to the
MW(kDa)
205-
116-
92-
66-
Fig. 7. Autorad~ogram of the binding of [z251~VIPto choroid plexus
epithelial cells, cross-linked to the receptor with disuccimidyl propionate and run overnight on a 7.5% SDS gel. The receptor has an
apparent molecular weight of 55 kDa. The three lanes represent,
from left to right, total binding of [‘2511VIP and binding in the
presence of lo-” M unlabelled VIP and PHI, respectively. The
position of the molecular-weight markers are indicated to the left.
Reproduced from ref. 249, with permission.
choroid plexus twofold. That both noradrenaline and
VIP stimulate CAMP production in choroid plexus
epithelial cells and lower CSF production25’, in combination with the VIP-mediated presynaptic enhancement of noradrenaline re1ease248, is interesting in view
of the synergistic actions of these two neurotransmitters demonstrated in the CNS103,213.It is possible that
such synergism exists also in the choroid plexus.
Information on other peptide neurotransmitters
in
the choroid plexus is more scarce. Neuropeptide Y
(NPY) has been demonstrated in rat, guinea-pig, rabbit, cat, pig and human choroid plexus by immunohistochemistry and radioimmunoassay (RIA)X9,247. NPY
I
sY
70
%
#m
60 t
ii
40
‘-
z
c!
'II
i!!
30
g
10
I
l **
T
I
20
"Id
=
0
.E
-10
ii
ii
-20
;c
-30
Fig. 8. Maximum effects of VIP, PHI, NPY (all three at IO-’ M) and
the a,-receptor antagonist yohimbine (3.10-s M) on the release of
[ ‘Hlnoradrenaline (NA) from sympathetic nerves in the pig choroid
plexus. All values are means + S.E.M. Statistically significant differences, as measured by the Student’s c-test for paired observations
are shown as * P < 0.05,
** P < 0.01,
** * P < 0.001. The enhancing
effects of VIP and PHI on [“H]noradrenaline release is in the same
range as the effect of yohimbine which blocks the inhibitory effect of
endogenous noradrenaline released from the sympathetic nerves.
levels measured by RIA were generally consistent between species, approximately 10 pmol/g in pooled
plexus tissue from all ventricies247. In contrast, immunohistochemistry revealed large differences in the
density of NPY-immunoreactive
nerve fibres, with a
moderate supply in pig and rabbit and a lower amount
in rat and guinea-pig 247. Technical problems, e.g., fixation time, might explain the discrepancies, but extraneuronal sources of NPY cannot be excluded, e.g., by
uptake or synthesis of NPY in the epithelium.
NPY is well known to coexist with noradrenaline in
sympathetic nervesy’~27h7but has also been demonstrated in non-sympathetic nerves, including nerves of
controi
VIP
Id3M
VIP
to.’M
Fig. 9. Relative changes in cerebrospinal fluid (CSF) production
(open bars) and choroid plexus (CP) blood flow (filled bars; measured by laser-doppler flowmetry) during the second perfusion period of a ventriculocisternal perfusion experiment, compared to the
initial perfusion period, with or without (control) intraventricular
administration of VIP. The figures within parentheses are the number of experiments in each group. All values are means*S.E.M.
Statistically significant differences, as measured by Student’s f-test
for paired observations are shown as * P < 0.05,
** P < 0.01.
Reproduced from ref. 251, with permission.
the cerebra1 circulation 'J1.105.l15.12~1.1t(2.22~.1.17..~.:i
. Light microscopical immunohistochemist~
in the choroid plexus
has shown two populations of NPY-immunoreactive
nerve fibres: (1) a minor population harbouring NPY
and the noradrenergic marker enzyme dopamine P-hydroxylase (DBH) and (21 a major population of nerve
fibres where NPY, VIP and PHI coexist2”. Denervation studies demonstrated a non-significant reduction
of 30% in NPY-content measured by RIA after sympathectomy in rabbit, while nerve fibres demonstrated by
immunohist~hemist~
were completely abolished2~‘.
The only functionaf data for NPY in the choroid
plexus to date is a slight inhibition by 10% of [“HInoradrenaline release from sympathetic nerves in the pig
choroid plexus evoked by electrical stimulation24”. This
presynaptic inhibition of noradrenaline release by NPY
has previously been demonstrated in several peripheral
tissues8232y7,“0”.
NPY inhibits CAMP formation induced
by isoprenalin and VIP in what is believed to be a NPY
receptor-mediated
mechanism via activation of an inhibitory G-protein 24. It is possible that similar interactions between noradrenaline, VIP and NPY occur in
the choroid plexus.
Low levels of substance P immunoreactivity, shown
by immunohistochemistry
and RIA, have been reported in the choroid plexus’*. These results could not
be confirmed in our laboratory247.
5. ENDOCRINE REGULATORY MECHANISMS IN THE
CHOROID PLEXUS
Hormones are traditionally described to be released
from their site of origin and traveI with the blood to
their target tissue, so called endocrine signalling. Also
the CSF seems to be a signalling pathway for transport
of ‘hormones’ from their site of synthesis to their
target cells”“‘. Theoretically, a hormone can pass from
blood to CSF (via the choroid plexus or brain regions
lacking a BBB) and reach the whole or parts of the
brain via bulk flow and diffusion to the brain extracellular fluid’sy~3”‘*3hX.
Hormones can also be synthesized
in the choroid plexus or meninges, secreted to the CSF
and reach the brain as above252. Alternatively, substances synthesized in a brain region can diffuse to the
CSF to reach another part of the brain by bulk
flow 2513,368* Evidence exists that the choroid plexus is
intimately involved in several of these processes, as will
be discussed in this and the following sections.
Advances in receptor autoradiography and immunohistochemistry together with traditional binding methods have revealed a great number of different neurohumorai receptors in the choroid plexus. In some cases,
e.g., the 5-HT,, receptor, the receptor concentration is
119
the highest in the whole brain’40~370.Receptors for
endocrine mediators in the blood or CSF, identified so
far, are summarized in Table I. While methodological
advances have made it possible to determine the presence, synthesis and characteristics of both the hormones and their receptors, functional studies of hormone action often suffer from the use of ‘non-physiological’ concentrations and routes of administration.
This is particularly important as several peptides show
a sharp peak in concentration for maximum effect90,153.
The choroid plexus contains large amounts of the
receptor subtype143~266~370,
with levels 10 times
higher than other brain regions, as revealed by
receptor
autoradiography
and in situ hybridization’40,‘66v230*267.
The 5-HT,, receptor is a G-proteincoupled receptor I@‘,structurally and pha~acologically
similar to the 5-HT, receptor’32,277 and acts on the
cellular level by hydrolysis of phosphoinositides4’~‘~
without affecting adenylate cyclase activity260.
The S-HT,, receptor appears to be localized to the
apical membrane of the choroid plexus epithelial
Chemical denervation of the 5-HT innervacells i17*131.
tion of the brain by centrally injected 5,7-dihydroxytryptamine induced a marked receptor supersensitivity
in the choroid plexus48, indicating that centrally released 5-HT influences the choroid plexus. Although
raphe-lesions
produce a pronounced
decrease in
choroid plexus 5-HT234, immunohistochemical
and
[3H]tryptamine uptake studies have been unable to
demonstrate
nerve fibres containing 5-HT in the
choroid ple~s433%250,327. Instead there is a very rich
plexus of 5-HT nerve fibres on the surface of the
ventricular ependyma, without apparent contact with
the ependymal celIs43,250*327.
Thus the fall in choroid
plexus 5-HT levels after lesion of the raphe nuclei234
probably reflects decreased reiease of 5-HT into the
CSF followed by a parallel decrease in 5-HT uptake in
the choroid plexus337,33X,34’.
All things considered, we have proposed a model
where 5-HT released from the supraependymal nerve
fibres diffuse into the CSF337,338and is taken by bulk
flow to the CSF side of the choroid plexus epithelium
where it interacts with the apically located 5-HT,,
receptors*” (Fig. 10). Comparison of cisternal 5-HT
levels in the rat with the dissociation constant (Ku)
of the 5-HT,, receptor is consistent with this hypothe5-i-IT,,
sis12,370
In cultured rat epithelial cells from the choroid
plexus, 5-HT increases the gene expression and synthesis of the plasma protein transferrin349. This effect
could be mimicked by a 5-HT,,-specific agonist but not
Fig. 10. Schematic picture of the rodent brain, showing a possible
pathway for 5-HT influencing the choroid plexus (only the choroid
plexus of a lateral ventricle is shown). Nerve fibers originating in
serut~ergie neurons of the raphe nuclei project to the yenta
of
all four ventricles, te~inating in a dense supraependymal plexus in
direct contact with CSF. Released 5-HT might diffuse into the CSF
and reach the choroid plexus by bulk flow. Reproduced from ref.
250, with permission.
blocked by corresponding 5-HT,, receptor antagonists,
indicating that this effect was not mediated by the
5-HT,, receptor or could be elicited in the presence of
minimal receptor occupancy348. In monkeys and dogs,
intravenous infusion of 5-HT increased choroid plexus
blood flow by lo-200%
without affecting cerebral
blood flow9*. Ventriculo-cisternal perfusion in rabbits
showed that intraventricular administration of 5-HT at
relatively high concentrations (10-7-10-5 M) inhibits
CSF production by 30 - 40%202,203.The effect could
partially be blocked by the 5-HT, receptor antagonist
ketanserin and the pi receptor antagonist practolol
and was completely blocked by the specific 5-HT,,
antagonist mesulergine202,203. Considering the relatively
high concentrations used, an effect via the noradrenergic pi receptors cannot be excluded. However, in rats
the partial 5-HT,, receptor agonist SCH-23390 has
also been reported to decrease CSF production34.
The physiological function of the 5-HT,, receptor
might not be related to those described above. Banks
and Kastin” proposed that the diurnal rhythms of
opiate peptides and the tetrapeptide Tyr-MIF-1 codd
partially be ascribed to diurnal variations in transport
rate of these peptides over the blood-CSF barrier and
BBB and later demonstrated that 5-HT could inhibit
transport of Tyr-MIF-1 out of the brain” (Fig. 11).
These findings correlate with the night-time peak levels of 5-HT observed in CSF”’ and it is possible that
the 5-HT,, receptor mediates an inhibition of TyrMIF-1 transport from CSF at night to increase the
levels in brain. If this is the case, then increased
activity in a neuronal pathway could lead to overflow of
a neurotransmitter, which will diffuse into the CSF and
be transported to target areas along the CSF pathway
as well as being absorbed into the blood as a part of
the sink action of CSF65J50.
choroid plexus epithelial cells in a manner consistent
with the presence of H, histamine receptorss”.‘5. Histamine enhances the passage of blood-borne “K into
the CSFX”, while no effect was seen with histamine on
rabbit CSF production measured by ventriculocisternal
perfusion (Lindvall-Axelsson,
unpublished observations).
Wlo
tnmol/mousc)
ICV
Fig. 11. Effect of various doses of serotonin (black bars), atropine
(hatched
bars) and carbachol
(grey bars) on the brain to blood
transport
of [ ‘251]Tyr-MIF-l.
* P < 0.05. An average of ten mice
were used per group. Reproduced
from ref. 16, with permission.
5.2. Mela tonin
Melatonin is secreted by the pineal gland, an endocrine gland located in the posterior part of the third
ventricle and partially in contact with the CSF”‘“. The
most prominent feature of melatonin is its diurnal
rhythm in blood and CSF with high nighttime levels
exceeding daytime concentrations severalfold’“,282, and
appearing to be especially high in the lateral ventricle
CSF as compared to cisternal CSF and jugular vein
plasma”‘“. Central binding of melatonin occurs in a few
discrete regions, notably the suprachiasmatic nucleus,
median eminence and retina’77,‘s5, where it inhibits
CAMP production via a pertussis toxin-sensitive G-protein’“. In the rat choroid plexus, receptor binding has
been reported in the caudal region of the fourth ventricle choroid plexus”‘5, while chronic administration of
melatonin in the hamster appeared to stimulate fluid
secretion in the lateral ventricle choroid plexus (but
not those of the third or fourth ventricle) as determined by electron microscopy and morphometry”6.
These results are interesting in relation to the recently
described circadian variation in human CSF production2.53
5.3. Histamine
Histamine decarboxylase-immunoreactive
and histidine decarboxylase (HDC)-immunoreactive
cells with
processes of varying number and length have been
described in the rat choroid plexus, with morphology
and distribution differing from that of mast cells24”,
although these findings were not confirmed by in situ
hybridization using a probe towards HDC mRNA42.
The function of these cells is unknown, but histamine
can stimulate CAMP production in cultured bovine
5.4. Atria1 and brain natriuretic peptide
The atria of the heart synthesize and secrete atrial
natriuretic peptide (ANP) which has an important role
in the fluid balance of the body, with diuretic, natriuretic and vasodilatory actions and interactions with
angiotensin II and aldosterone (for reviews, see refs.
113,151). ANP is also present in neurons of the brain
where it appears to function as a central neuromediator”24,“67and can be found in the CSF at levels of 0.5-l
PM. concentrations independent of the higher plasma
concentrations2’“~22”~222.Binding sites for ANP are present in many brain regions including the brain capillaries and choroid plexus2Y~“h~2’h~27X,
the apparent binding
concentrations in the choroid plexus being among the
highest in the brain 2y2. The ontogeny of these binding
sites in rat brain show that while high levels of binding
of ANP only occurs in the cerebral cortex in fetal and
neonatal life and thereafter diminishes drastically, the
binding sites in the choroid plexus and other circumventricular organs increase gradually after birth and
reaches maximum levels postnatally’““. Interestingly,
the increase in ANP binding parallels the gradual
increase in CSF production seen after birth in rats”‘.
The binding sites found in the choroid plexus I ave
been identified as an ANP-binding particulate guanylate cyclase”4~4’~‘7X~2ys.
ANP and the related brain natriuretic peptide, has been shown to stimulate cyclic
GMP production in the choroid plexus”2,.14” and ANP
reduces CSF production in rabbits”2h. Inhibition of
CSF production might occur through inhibition of
amiloride-sensitive Na+ transport, as demonstrated in
cerebral capillaries”‘. Furthermore, ANP injected intraventricularly during hypoosmolar fluid loading led
to sodium loss and water accumulation in the brain7x,
indicating that ANP has a general role in brain fluid
balance. In addition, ANP is rapidly degraded by the
choroid plexus, as well as the pia mater, through the
action of neutral endopeptidase 24.11 which is located
at the apical brush border of the choroid plexus epithelial cells”2.
Normal CSF levels of ANP (0.5 - 1 pM) are far
below the association constant (K,,) reported for the
ANP receptor binding and guanylate cyclase stimulation in the choroid plexus’2h,34”,and it seems likely that
the ANP receptors in the choroid plexus are not acti-
121
pressure balance in the brain, with the choroid plexus
and CSF production as one component.
Fig. 12. Autoradiographs showing [ ‘251]atrial natriuretic peptide
(ANP) binding sites in the choroid plexus of 3-week-old rats with
congenital hydrocephalus (LEW-HYR and HTX rats). In LEW-HYR
rats, the extent of the dilatation of the lateral ventricle was divided
into three subgroups: marked (I), medium (II) and slight (III).
Arrows indicate the presence of [‘*‘INNP binding sites in the
choroid plexus. Reproduced from ref. 232, with permission.
vated during physiological conditions. This might occur
in several diseases, however. ANP binding sites are
increased in kaolin-induced, but lowered in congenital,
hydrocephalus 232,347(Fig. 12) and ANP levels in the
CSF are higher in patients with raised intracranial
pressure79. Brattleboro rats with hereditary diabetes
insipidus (lack of vasopressin) showed no changes in
ANP binding**‘, while the number of binding sites for
ANP were lower in the choroid plexus and brain capillaries of spontaneously hypertensive rats, a rat strain
that also shows dilated ventricles’47~232~258~292,293.
These results indicate that atria1 and brain natriuretic peptides might be involved in volume, ion and
5.5. Vasopressin
Vasopressin, often specified as arginine vasopressin
(AVP), is a well-known nonapeptide neurotransmitter
in neurons
located
in the hypothalamus projecting to
the neurohypophysis where AVP is released into the
blood stream. In addition, AVP has been demonstrated immunocytochemically
outside the hypothalamo-neurohypophyseal
system and binding sites exist
in many areas of the brain, including the choroid
plexus114~27’~356~357.
The AVP receptor found in the
choroid plexus appears to be of the V, subtype, which
stimulates phospatidylinositol hydrolysis and appears
to bind AVP, and the related peptides oxytocin, vasotocin and the AVP metabolite AVP,_,, with high affinity (1 nm <K, < 3 nM)3h,356. Tribollet et a1.“44 also
demonstrated high binding of AVP to V, receptors in
the choroid plexus but could not detect binding of
oxytocin. These results clearly show that the choroid
plexus is a target for AVP, although whether of central
or peripheral origin (or both) has not been determined,
see further below.
Rudman and Chawla extracted a peptide with antidiuretic properties from mammalian choroid plexus
which could be identical with AVP290, and two AVPcontaining neural pathways from the hypothalamus to
the lateral ventricles and choroid plexus fissures have
been described37,38. In the study by Brownfield and
Koslowski37, no fibres inside the choroid plexus itself
were reported and the findings may parallel those we
have made for 5-HT-immunoreactive nerves, i.e. nerve
fibres supply the ventricle walls and reach the base of
the third and lateral choroid plexus at the choroid
fissures but do not penetrate into the actual choroid
plexus tissue 202~250.
However, AVP might be released in
the vicinity of blood vessels”’ supplying the choroid
plexus and directly into the CSF. In fact, AVP is
present in CSF with a concentration gradient from the
third ventricle to the cisterna magna313,3h8,the concentrations showing a more or less prominent circadian
rhythm in all non-human species studied’1,304, this
rhythm apparently being weak or absent in humans10,318.Also, the CSF AVP levels are not coupled
to changes in plasma AVP, demonstrating their different sites of release’80~227~319.
Incidentally, oxytocin concentrations showed a time-dependent peak in CSF of
humans’. The presence of AVP in the CSF and lack of
evidence for a direct innervation of the choroid plexus
by AVP-containing nerves lead us to believe that the
antidiuretic activity present in the choroid plexus is
due to uptake from blood or CSF.
122
2
z
o--
299
Plasma
3’0
330
Osmolality
350
370
390
(masmol/kg)
Fig. 13. Increases
in [“Cojdiethylenetriaminepentaacetic
acid
(DTPA) clearance
from CSF to brain as a function
of plasma
osmolality in Long-Evans
(closed circles) and the genetically vasopressin-deficient
Brattleboro
strain of rats (open circles). The graph
shows how the clearance of [“COIDTPA
is lower in vasopressin-deficient animals, which also have a lower CSF production.
Reproduced
from ref. 68, with permission.
While the source and regulation of AVP levels in
the brain and CSF is still a matter of debatezO%“s, this
review will deal primarily with the effects of AVP
related to choroid plexus and CSF function. It is reasonable to assume that AVP is involved in brain ion
and volume homeostasis, as has previously been suggested*s”. In general, AVP appears to increase the ion
and water content of the brain while AVP has the
opposite effect 5y. Increases in CSF osmolality are followed by an increase in AVP concentrations in the
CSF2”“,“34*358.
This could be a compensatory response,
as AVP increases capillary permeability and brain
water77*280~2X6
and might mediate bulk flow of CSF
water and electrolytes into the brain59*68,285(Fig. 13).
Ultrastructural studies of choroid plexus epithelium
after incubation with low concentrations of AVP (1O-‘2
M) suggest that AVP indeed might increase CSF production by the choroid pIexus205,307and CSF production has been reported to be lower in the AVP-deficient Brattleboro strain of rat@. On the other hand,
direct measurements of CSF production by ventriculocisternal perfusion showed an inhibition of this parameter by 20-50%, suggested to be mediated by VI-receptorsh4,““‘. These results could be explained by the drastic decrease in choroid plexus blood flow (up to 70%)
by a V, receptor mechanism seen during intravenous
infusion of AVPy7*‘oo. The report by Schultz et al.“‘*
that dehydration and subcutaneous administration of
AVP produced an ultrastructural
response in, the
choroid plexus characteristic of a decrease in CSF
production could be explained as secondary effects of
the dehydration and blood flow reduction, respectively.
Dehydration increases AVP levels in plasma but not
CSF”‘“.
Effects of intraventricular AVP on intracranial pressure are inconclusive as the intracranial pressure has
been reported to increase after AVP administration in
goats”“5, while the pressure in rabbits was lowered by
AVP in another study, a decrease suggested to be
mediated by facilitated drainage of CSF through the
arachnoid granulations2’4.“‘. Although CSF levels of
AVP have been reported to be higher in patients with
raised intracranial pressure”X,720,“2’, this could be a
mechanism to compensate for the lowered water content of the hydrocephalic brain6’. In addition, one
should be cautious when interpreting levels of substances in the CSF, as changes in the production rate
of CSF will affect the concentration of the measured
substance even if the secretion of this substance remains unchanged’64x”‘h. In this case, a decrease in CSF
production as a response to the increase in intracranial
pressure would probably result in an increase in AVP
levels in CSF in the face of normal AVP secretion.
That AVP and ANP seem to mediate opposite effects
on many systems in the body and that ANP and brain
natriuretic peptide inhibit AVP secretion3” is also an
indication that AVP actually increases fluid secretion
from the choroid plexus. This should be studied using
low concentrations of AVP administered intraventricularly. Finally, other functions for AVP in the choroid
plexus have been suggested by the observation that
AVP enhances the clearance of /3-endorphin from rat
CSF”““. For an extensive review on the subject of AVP
in CSF, see ref. 31X.
5.6. Angiotensin
II
In addition to AVP, ANP and brain natriuretic
peptide, angiotensin II is another important factor in
the regulation of brain water and electrolytes*‘“. The
choroid plexus may be a component in a brain angiotensin II system, as high concentrations of both
renin314 and angiotensin-converting enzyme’4.4y.‘2x are
present in this organ, as are angiotensin II receptors’,“*. Interestingly, CSF production increased during ventriculo-cisternal
perfusion with a potent inhibitor of angiotensin-converting enzyme”‘“, suggesting
an inhibitory role of angiotensin II on CSF production.
Intravenous infusions of angiotensin II resulted in a
pronounced decrease in choroid plexus blood flow in
rabbits, with no change in cerebral blood flow, using
the radioactive microsphere technique2”. In contrast,
no change in choroid plexus or cerebral blood flow
during angiotensin II infusion intravenously could be
seen with [ “Hliodoantipyrine
autoradiography
in
rats”“.
123
5.7. lizsulinand insulin-likegrowth factors
Insulin, insulin-like growth factor-1 @F-I) and insulin-like growth factor-II (IGF-II) bekmg to a structurally conserved family af peptides with widespread
metabolic and trophic effects in the body (for reviews,
see refs. 62,108,298). Both IGF-I and IGF-II are
synthesized
in most fetal tissues, including the
brain2~,u6*289, while in adults IGF-I synthesis and secretion to plasma occurs in the liver and IGF-II mRNA
is limited to the brain, more specifically the choroid
plexus and meninges25*‘4~~‘49~32p.
The expression and
function of @F-II in the choroid plexus will be discussed in detail in subsection 6.1. Three types of receptors for insulin and IGFs exist’“‘. The type I IGF
receptor (or IGF-I receptor) is a tyrosine kinase receptor which binds both IGF-I and IGF-II with high
affinity, This receptor is structurally similar to the
insulin receptor which binds insulin and IGF-II Gin
order of potency). The type II IGF receptor [usually
designated the mannose 6-phosphate/IGF-II
(Man 6P/IGF-II) receptor) has two binding sites for mannose
6-phosphate and IGF-II, respectively231 and appears to
be a clearance receptor targeted to lysosomes, but with
possible metabolic effects as welf287, The Man 6P/IGF-II receptor does not bind IGF-I or insulin.
All three receptor typ&a;e present ih the choroid
Receptor binding studies in difplexus 22,63,139,183,252,353.
ferent fractions of purified epithelial cells from pig
choroid plexus showed that high levels of IGF-I receptors could be found on the surface of the epithelial
cells, as demonstrated by high binding on whole cells
and especially in the clathrin-enriched, Triton X-lOOinsoluble fraction50p252. In contrast, Man 6-P/IGF-II
and ins&in receptors were mainiy found in a soluble,
intracellular pool %‘. The larger number of IGF-I receptors compared to insulin receptors was recently
demonstrated by quantitative receptor autoradiography
in rat brain as welI’j3.
The function of the IGF receptors in the choroid
plexus is largely unknown, while some i~fo~ation
is
available for the insulin receptor. One possibility is
that the insulin receptor participates in transcytosis of
insulin from blood to CSF21*303,as has been suggested
for the brain capillaries where such transport from
blood to brain extracellular fluid might occur via a
receptor-mediated
mechanism6~,‘06,157,173”
Changes in
the plasma concentration of insulin are reflected in the
CSF, although with a considerable delay369. Furthermore, insulin injected in the CSF of the lateral ventricles reaches neurons in the h~othalamus
and thalamus but not the cerebral cortex”. Direct actions of
insulin on the choroid plexus epithelium have also
been reported. Insulin, as well as IGF-I and IGF-II,
Total ATPaoe
NaK-ATPase
T/M Cholme
mproductior!
L/18
Fig, 14. Effect of treatment with betamethasone phosphate for 5 days
(stippled bars) on CSF production in rabbits fexpressed as &minf
and on activities of total ATPase, Na+-Kf-ATPase (expressed as
nmol/mg protein/min) and tissue/medium ratio (T/M) of choline
(expressed as activity related to mg protein per ~1 medium of
radiolabelled choline) in rabbit choroid plexus from lateral ventricles
compared with. tissue from control animals (open bars) receiving
vehicle only. Values are meansrfrS.E.M., number of animals indicated. Student’s f-test: * P < (1.05; *’ 0.001< P < 0.01; * ** P <
0.001 vs controk.
stimulated tyrosine kinase activity in glycoproteins extracted from pig choroid plexus epithelial ~ells~~~and
insulin also accelerated basolateral Na+ transport in
viva in rat choroid plexus epithelium without increasing apical Na+ extrusion, thus probably not affecting
CSF productian16’.
GIu~rticoids
have been widely used in neurosurgery because they counteract brain edema and intracranial hypertension, but the mechanism behind
these effects are not completely understood, WhiIe
some studies demonstrated a marked. reduction in CSF
production after acute intravenous administration of
glucocorticoids in dog6*299,361,
others found no effect in
monkey and dog, respectively2’8V362.In a study in rabbit
by Lindvall-Axelsson et al. ‘04, there was a pronounced
decrease in CSF production (43%) upon treatment for
5 days with betamethasone phosphate, accompanied by
a reduction by 30% in Na’/K+-ATPase
activity and
choline uptake in the lateral plexus as well (Fig. 14).
This indicates that an inhibition of Naf-pumping from
the choroid plexus epithelium to the CSF is the mechanism of action behind glucocorticoid-mediated
inhibition of CSF production, which might partly explain the
beneficiai effects of glucocorticoids in patients with
intracranial hypertension.
The main endogenous gIucocorticoid is cortisol, a
prominent stress hormone, which exerts its effect by
binding to intracellular receptors and changing gene
transcription in various cell types in the bodyllg.
Whether cortisol has any physiological actions on normal choroid plexus function is not known, but it might
124
stimulate the maturation of certain transport systems
in the choroid plexus during pre- and postnatal development, i.e. having opposite effects on young animals
compared to adults (Lindvall-Axelsson et al., unpublished results). No change in IGF-II gene expression
was seen in the choroid plexus with cortisone acetate
treatment while liver IGF-II mRNA was markedly
diminished2’.
5.9. Sex steroids and thyroid hormones
Combined treatment of rabbits with 17-@-oestradiol
and progesterone
has been shown to decrease
Nat/K+-ATPase
activity in the choroid plexus and
choline uptake in the lateral ventricle plexus’““. The
mechanism behind this effect is not known but has
been suggested to be direct stimulation of oestrogen
receptors by the combined treatment in choroid plexus
epithelial cells, an interaction between aldosterone and
progesterone at cellular receptors or an upregulation
of P-receptors in the same cells under the influence of
progesterone’““. Cranial CSF volumes in women, measured by magnetic resonance imaging, increase premenstrually, indicating either a stimulation of CSF
production by the surge of progesterone, 17-hydroxyprogesterone (and to a lesser degree 17-p-oestradiol)
or a decrease in brain and/or cranial blood volume”“,““‘. Oestrone has also been suggested to increase CSF production, based on the high CSF levels
of oestrone coupled to low protein levels seen in obese
female patients with pseudotumour cerebri, a disease
characterized by diplopia, loss of colour vision, decreased visual acuity and headaches’. The symptoms
and oestrone levels were suppressed by dexamethasone
treatment. Clearly, the effects of sex steroids on brain
fluid dynamics are poorly understood, in spite of the
intracranial symptoms reported and suggested premenstrually (for further references, see above).
The choroid plexus could also provide a pathway for
sex steroid hormone targeted to the CSF and brain,
considering the presence of sex-hormone-binding globulin in CSF272. Glucocorticoids and sex steroids are
transported into CSF from blood to an extent determined by the amount of free hormone in serum**‘.
Treatment of rats with the thyroid hormone triiodothyronine (T,) has been shown to inhibit choline
uptake by almost 70% while stimulating Na+/K+ATPase activity s1ightly2”‘. In the same study, hypothyrodism, induced by treatment with propylthiouracil,
inhibited Na+/K+-ATPase
activity but was without
effect on choline uptake. The mechanism behind these
actions are not known but might involve upregulation
of P-receptors and could be of importance in patients
with thyroid dysfunction.
As mentioned above, the choroid plexus synthesizes
large amounts of the thyroid hormone carrier protein
transthyretin and secretes it into the CSF”‘“,““. The
importance of this synthesis for thyroid hormone transport to the CNS will be discussed in subsection 6.4.
5.10. Other mediators
As shown in Table I many other neuroendocrine
mediators have receptors in the choroid plexus. Below,
some of these mediators with demonstrable functional
effects are discussed briefly.
Most interesting is probably the recently isolated
600 dalton compound with digitalis-like properties isolated from human CSF’24.‘2’*‘Xs.This substance appears to be an endogenous Na+/K+-ATPase
inhibitor’” and a potent inhibitor of CSF production as
demonstrated in t’iz’o in rabbit2”‘. Expansion of the
extracellular fluid volume by intravenous infusion of
isotonic saline in humans resulted in increased CSF
levels of this substance”“.
Dopamine receptors of the D, subtype are present
in the choroid plexus 2-244
. The presence of strong immunoreactivity for the dopamine- and cyclic adenosine3’,5’-monophosphate
(CAMP)-regulated phosphorprotein DARPP-32’“s indicates that dopamine can regulate choroid plexus function. Dopamine-containing
nerve fibres have not been reported to be present in
choroid plexus tissues and dopamine acting on the
choroid plexus might be mediated via the CSF as has
been suggested for 5-HT”“.
Endothelin is a potent and long-acting vasoconstrictor peptide located in both vascular endothelial cells,
neurons and CSF”0,“42,“7’. High levels of endothelin
binding sites are present in choroid plexus of both the
lateral and third ventricles’h2.‘7” and endothelin decreases choroid plexus blood flow after i.v. administration’h7.
The finding that benzodiazepine receptors are present at high levels in the choroid plexus is of unknown
physiological significance as only high concentration
(10-h-10-4 M) inhibited CSF production, without any
effect on CAMP levels or ATPase activity”h4.
6. THE CHOROID PLEXUS AS SOURCE AND PATHWAY FOR ENDOCRINE SIGNALS TARGETED TO
THE BRAIN
6.1. Insulin-like growth factor-II
The polypeptide hormone IGF-II described above
in subsection 5.7 shows widespread synthesis in most
fetal tissues2”9,289,while IGF-II mRNA in the adult
predominates in brain2”6. Further studies of IGF-II
mRNA localization in rat brain by in situ hybridization
125
must therefore be considered (see also the discussion
could only show IGF-II expression in the choroid plexus
and meninges25,146,149,329,
on TTR below in subsection 6.4.).
although low expression not
detectable by this method might be present in the
6.2. Prolackin
brain parenchyma as well 149.The same situation apThe choroid plexus is enriched in prolactin binding
plies to the adult pig, where northern blot hybridizasites275Z54.As the CSF concentration of prolactin retion of Poly A + mRNA detected IGF-II mRNA in
flects that of serum in what appears to be a saturable
extracts from choroid plexus and meninges but not in
transport mechanism27~2~~2’i~217,the choroid plexus
other parts of the brain fBlay et al., unpublished obserprolactin binding sites have been suggested to be invations). It is possible therefore that previous findings
volved in transport of prolactin from blood to
of mRNA in brain tissue were due to contamination by
CSF211,243,312.The function of this transport system
choroid plexus and meninge?.
could be a negative feedback loop to inhibit prolactin
Although direct evidence is not available for IGF-II
secretion either at the level of the dopaminergic cell
secretion into the CSF, as has been shown for TTR301,
bodies in the hypothalamus or their nerve terminals in
IGF-II is present in CSF in two different forms’33
the median eminence211y243,This transport concept is
together with an IGF-binding protein with selectivity
supported by the finding that in vivo labelling of the
for IGF-II which is also synthesized in the choroid
hypothalamus after intravenous injection only occurs
plexus’42,~6.34~_w e h ave recently demonstrated secreafter choroid plexus prolactin binding sites have develtion of IGF-II and IGF-binding protein by sheep
oped on day 14 postnatally312. A direct action of prochoroid plexus epithelial cells in primary culture (Hellactin on the choroid plexus epithelium has also been
lesen et al., in preparation). IGF-II is also found in
suggested275.
significant amounts in the brain parenchyma41,‘34. The
brain is obviously a target tissue for IGF-II as IGF-I,
6.3. Other peptides
Man &P/IGF-II
and insulin receptors (all of which
Transport systems in the choroid plexus for endogebind IGF-II) are present on brain cortical plasma
nous peptides produced either centrally or peripherally
membranes’09~110in widespread areas of the brain’39~‘83.
have not been characterized to any greater degree,
Several functional effects for IGF-II have been repartly due to difficulties in separating transport from
ported on cells of the CNS, mediating both endocrine
uptake and degradation. Furthermore, many studies do
and neurotransmitter
roles for IGF-IIg3~‘74~‘8’*223~235~281;
not distinguish between transport of peptides over the
The question arises if the IGF-II acting on CNS
BBB and the blood-CSF barrier. For recent reviews
IGF-receptors
is derived from the CSF, plasma or
and references we refer to Banks and Kastin’5J7J8.
both. Receptors for IGFs have been demonstrated on
endothelial cells of the BBB, but evidence for a role of
6.4. Transthyretin and the transport of thyroid hormones
these receptors in transcytosis of IGF-II (and IGF-I)
to the brain
from blood to the brain extracellular fluid is lacking2’j5,
The plasma protein TI’R is an important carrier of
although such transport
has been suggested for
thyroid hormone, as shown by its presence and thyroid
insulin69*‘06V’57~173.
The possibility that the choroid
hormone-binding
capacity in mammals, birds, and
plexus and meninges are secreting IGF-II into the CSF
reptiles130,26g.In contrast to thyroxine-binding globulin,
for transport by bulk flow and diffusion to the CNS
which is only present in larger mammals, complete
Liver
Dilutions
1
“Rest
of
Brain”*
2
“Rest
of
Brain”
3
Choroid
Plexus”
4
Choroid
Plexus
5
* RNase
Treated
Controls
Fig. 15. Dot-blot determination of mRNA for transferrin (A), trans~~etin (preaIbumin) (B) and albumin (C) by h~~~~ation to specific cDNA.
Row 1, cytoplasmic extracts ~rresponding to 2500, 1000, 500, 250, 100, 50, 25 and 10 &g liver, wet weight, per spot. The extracts used in rows
2-5 were prepared from the tissue of seven individual animals and processed separately. Rows 2 and 3, cytoplasmic extracts corresponding to
2500 pg of brain tissue, wet weight, per spot, excluding choroid plexus. Rows 4 and 5, cytoplasmic extracts corresponding to 500 fig choroid
plexus per spot. Rows 2 and 4, cytoplasmic extracts incubated with ribonuclease prior to processing for hybridization. The very high expression of
transthyretin mRNA, compared to liver, is clearly evident. Reproduced from ref. 72, with permission.
126
deficiency of TTR appears to be incompatible with life
in higher vertebrates ‘by. Furthermore, TTR is the dominant carrier of Td in the CSF of both rat and
humans”“~‘2’, due to the higher proportion of TTR in
the CSF, in relation to the concentrations
of
thyroxine-binding globulin (when present) and albumin, compared to serum.
Among the many plasma proteins synthesized by the
choroid plexus, TTR is by far the most abundant,
constituting 20% of total choroid plexus protein synthesis and as much as 50% of the protein secreted
from the choroid plexus74. Expression of TTR or closely
related proteins in the choroid plexus is present in
all mammals, birds and reptiles investigated
so
far"_73.'.10.'55.325,372
and is a phylogenetically older phenomenon than TTR expression in the liver’““, with
levels in the choroid plexus being 11 times that of
liver3” (Fig. 15). In addition, TTR mRNA is present in
yolk sac and pancreatic islets’“7,15s.It has recently been
demonstrated unequivocally that choroid plexus TTR
is secreted mainly into the CSF and not to the blood
and that TTR in the CSF derives predominantly from
the choroid plexus12h,“0’. This explains why the
CSF :plasma ratio for TTR is much higher for TTR
than for albumin and many other plasma proteins”‘2,“60.
The high rate and exclusive localization of TTR
synthesis in the brain leads to the natural question of
TTR’s function in the CSF and its importance for CNS
function. TTR is a carrier protein for thyroid hormones and retinol-binding protein”” and thus could
function as a carrier for thyroid hormones (thyroxine
CT,) and, to a lesser degree, triiodothyronine (T,)) and
the retinol-binding
globulin/retinal
complex from
blood to brain. The choroid plexus accumulates [‘2511T,
in vitro and in vivo against a concentration gradient to
levels exceeding those of all other tissues in the body,
including liver “-‘*’
- . . Further study revealed that the
time-course of [‘251]T,-uptake into CSF closely followed that of the choroid plexus, while uptake into
cortex and striatum, less than 1% of choroid plexus
levels but similar to the CSF, was slower and did not
level off until 12-15 h after injection75.30’ (Fig. 16).
These findings have led to the hypothesis that T4
transport to the brain is mediated by high-capacity
uptake into the choroid plexus and secretion on the
apical side of the epithelium where T4 binds to newly
synthesized TTR. The TTR-T, complex is then transported by CSF bulk flow through the ventricle system
and the subarachnoid
space to reach the brain
parenchyma through the paravascular spaces”’ surrounding the penetrating arterioles from the pia mater
to the brain parenchyma3”‘. This is feasible as
horseradish peroxidase injected into the lateral ventri-
a,8OO
-
ChorOld
0’
0
12
6
0
.
’
6
.
’
12
Plexus
18
.
’
18
24
”
24
Hour5
Fig. 16. Kinetics of distribution of [ ‘251]thyroxine injected intravenously into rats. Top: radioactivity in choroid plexus (closed
squares), blood (open squares) and pituitary (closed triangles). Bottom: radioactivity in striatum (closed squares), cortex (open squares)
and cerebrospinal fluid (closed triangles). Values are means + S.E.M.
for four rats per time point. Reproduced from ref. 301, with permission.
cle CSF reaches the paravascular spaces and brain
extracellular fluid within minutes”“, probably facilitated by brain motion associated with the cardiac cycle,
although bulk flow of CSF into the brain via the
perivascular spaces is not supported by data using
other tracers15’.
The more active thyroid hormone T, is not accumulated specifically in the choroid plexus and is rapidly
taken up by all tissues after [‘251]T3 injection i.v.75,
probably due to a less ionized state at pH 7.4 than
Ti”. The results of several other studies fit quite well
with the above-described theory. Autoradiography of
rat brain sections after i.v. injection of [ ‘*‘IIT or
[‘251]T4 shows uptake into discrete neural systems of
the brain which for [1251]T4was dependent on brain
5’-deiodinase activity 83,84
. Furthermore, TTR has been
shown to bind to specific high-affinity receptors on
human astrocytoma cells ” . In an elegant and thorough
study Hagen and Solberg ‘*j demonstrated that while
T, had a brain extracellular fluid/CSF ratio of 50, the
ratio for T4 was 0.7. Correspondingly,
CSF/serum
steady-state distribution was reached after 240 min
constant i.v. infusion of T4 but not T,.
The theory put forward by Schreiber et al.““’ is not
without problems, however. Banks et al.‘” found that
127
[1251]T4 injected i.v. showed negligible entry into the
brain, while [1251]T4 injected in lateral ventricle CSF
was rapidly transported out of the brain by a saturable
transport mechanism. The half-time for this brain-toblood transport was 30 min, while the estimated rate of
transfer of exogenous TTR from CSF to blood was 0.35
TTR pools/h 214. No degradation of TTR was seen in
the nervous system 214. These results are similar to
those found in our laboratory and recently confirmed
by Dratman et aL8’, where rat brain sections were
examined autoradiographically
after i.v. and intraven-
tricular (i.v.c.> administration of [“‘I]T4. In these experiments we found weak staining throughout the brain
parenchyrna after i.v. injection while most of the [ lzI]T4
remained in the CSF spaces after i.v.c. injection from
where it gradually disappears with time without any
visible increase in brain radioactivity (Fig. 17). In addition, we found that cycloheximide treatment, which
efficiently inhibits protein synthesis without affecting
BBB permeability, actually increases the ,radioactivity
in brain cortex as shown by autoradiography (Fig. 17)
and direct gammacounting (Table II). A transport sys-
Fig. 17. Darkfield autoradiographic images of [lz51]Tq distribution in rat brain after intravenous (A, B) and intraventricular (C, D) injection,
respectively. In A and B, 3 PCi [lssIlrq (1200 &i/Kg) per 100 g body weight was injected intravenously in control rats (A) and rats treated with
the protein synthesis inhibitor cycloheximide (B) (0.2 mg/lOO g intraperitoneally) 2 h prior to injection. After 4 h the rats were decapitated, the
brains were dissected out, immersed in OCT compound and frozen in pentane on dry ice. Sections (20 pm) were cut in a cryostat and mounted
on coverslips and put together with 3H-Hyperfilm tAmersham in a X-ray cassette and exposed for 4 weeks. After i.v. injection in control rats,
the radioactivity could be seen at high levels in the lateral and third ventricle choroid plexus and very faintly in the meninges. No radioactivity
was detectable in the parenchyma (A). In contrast, cycloheximide-treated rats (B) showed lower levels of radioactivity in the choroid plexus, while
the cerebral cortex radioactivity (arrows) was increased, compared to controls (see also table II). In C and D, 1 &i [issIlT, in 5 ~1 saline was
injected into the lateral ventricle of 300 g rats. At different times after injection (5, 30 and 240 mini the rats were killed, the brains dissected out
and sectioned as above. The films were exposed for 10 and 30 days. Radioactivity above background levels could only be seen in the CSF spaces
(ventricles, cerebral aqueduct and subarachnoid spaces), irrespective of the length of exposure, with the amount of radioactivity declining with
time. The images shown in C and D is from a rat killed 30 min after intraventricular injection of [izsI]T,. A slight leakage of radioactivity from
the ventricle to the cortical subarachnoid space might also have occurred through the injection canal. The bars represent 5 mm.
128
TABLE II
EfJect
ofprotein synthesis inhibition on
T, uptake by bmirt tissues
The results are expressed as mean + S.E.M. (n = 5). Td uptake is
expressed as (dpms/mg tissue)/(dpms/Fl
blood). All rats were
killed 4 h after [‘2sI]T, injection. * = P < 0.05, * * = P < 0.01.
Tissues
Control
Cycloheximide
Choroid plexus
Cortex
Striatum
Cerebellum
Pituitary
6.62 +2.5
0.067 f 0.01
0.074 f 0.02
0.057 * 0.04
0.35 +0.1
2.98 +0.69 *
0.093 * 0.01 * *
0.092 + 0.01
0.069 + 0.03
0.33 +0.1
tern for both T, and T4 at the BBB has also been
proposed262.
Thus, it seems that the theory presented above
cannot explain the role of TTR in the CSF completely,
especially considering that only a few per cent of all
TTR molecules carry thyroid hormones in both CSF
and serum154. In the liver the thyroid hormone-binding
plasma proteins are necessary for an even tissue distribution of the hormones 226*263
(Fig. 18). We now propose a more complex model for the transport of thyroid hormones to the brain (Fig. 19). In this model T,
enters the brain through the BBB, while T4 enters via
the choroid plexus and CSF and possibly by BBB
transport as well. In the CSF, TTR binds 80% of the
Ti”‘. Part of the TTR, the TTR-T, complex and free
T4 will be removed by bulk flow of CSF and transported back to the blood. The remaining TTR, TTR-T,
and T4 will enter the brain through diffusion and bulk
flow as described above. In the brain, extracellular
fluid TTR facilitates the distribution of thyroid hormones to neurons and glia, possibly by binding to TTR
“I
-g
a0
(3
&
a
g
3
60
40
u
20
0
100
200
300
400
500
600
Distance from Portal Venule ( pm )
Fig. 18. Quantitation of the portal to central concentration gradient
of [‘251]T4 in rat liver after its single pass perfusion through the
portal vein in buffer (triangles) or serum (squares). All of the grains
in each grid square were assigned a distance from the portal venule
equal to that of the middle of the grid square; the number of grains
in each grid square was normalized to the grain density in the grid
square closest to the portal value (assigned a value of 100). Each
point shown is the mean *S.E.M. of determinations made in 15
lobules from three different livers. Reproduced from ref. 226, with
permission.
Fig. 19. A working model for thyroid hormone transport to the brain,
including the role of transthyretin (II”TR) in the cerebrospinal fluid
(CSF) in transport and distribution of thyroxine CT,) to the brain
parenchyma. See text for details. CP (choroid plexus), ECF (extracellular fluid), AG (arachnoid granulations), T, (triiodothyronine).
The thickness of the arrows represent the estimated quantity of a
substance in a certain transport route in relation to the other
pathways.
receptors on these cells. The more potent, but less
abundant, thyroid hormone T, thus readily reaches its
target cells by crossing the BBB, while T4, partly bound
to TTR, provides a pool of hormone in the extracellular fluid. The turnover rate of TTR in brain2’” is
compatible with the slow transport of high-molecularweight compounds in brain parenchyma184. In fact,
distribution of T4 throughout the brain extracellular
fluid would still be an important role for TTR even if
all T4 that reaches the brain is transported directly
over the BBB’59, as indicated from the study by Dratman et al.85. At the same time, the choroid plexusTTR-CSF system might constitute a rate-limiting step
for T4 transport to the brain. That the in vitro uptake
rate of T4 in the choroid plexus exceeds the rate of
release fivefold75 might support the latter view.
Another plasma protein, retinol-binding protein, is
also transported by TTR in the blood”‘. The choroid
plexus could act as a pathway for transport of retinol to
the brain considering the presence of cellular retinolbinding protein and receptor binding and internalization of serum retinol-binding protein in choroid plexus
epithelium 210. Whether serum retinol-binding protein
is synthesized in the choroid plexus has not been
clarified’54*2’0, but low levels of retinol-binding protein
mRNA
is present
in
RNA
extracted
from
whole
brain3”.
Finally, TTR might also be involved in intracerebral
transport
of substances
like noradrenaline
and serum
as has been shown in plasma. The
thymic factor”.”
suggested thymic hormone-like
activity of TTR”” and
its structural homology with the glucagon-secretin
peptide hormone family 165should also be considered.
129
RIA
SDS-PAGE
7. SUMMARY
The CSF is often regarded as merely a mechanical
support for the brain, as well as an unspecific sink for
waste products from the CNS. New methodology in
receptor autoradiography, immunohistochemistry
and
molecular biology has revealed the presence of many
different neuroendocrine
substances or their corresponding receptors in the main CSF-forming structure,
the choroid plexus. Both older research on the sympathetic nerves and recent studies of peptide neurotransmitters in the choroid plexus support a neurogenic
regulation of choroid plexus CSF production and other
transport functions. Among the endocrine substances
present in blood and CSF, 5-HT, ANP, vasopressin
and the IGFs have high receptor concentrations in the
choroid plexus and have been shown to influence
choroid plexus function. Finally, the choroid plexus
produces the growth factor IGF-II and a number of
transport proteins, most importantly transthyretin, that
might regulate hormone transport from blood to brain.
These studies suggest that the choroid plexus-CSF
system could constitute an important pathway for neuroendocrine signalling in the brain, although clearcut
evidence for such a role is still largely lacking.
Acknowledgemenrs. Parts of this study have been supported by grants
from the Medical Faculty of Lund, the Swedish Society for Medical
Research and the Swedish Medical Research Council (Grant no.
14X-732).
ABBREVIATIONS
ANP
ATPase
AVP
BBB
B
&ZIP
cGMP
ChAT
CNS
CSF
DBH
FITC
IGF
i.v.
i.v.c.
Ko
Man 6-P
mRNA
NA
NPY
PHI
atria1 natriuretic peptide
adenosine triphosphatase
arginine vasopressin
blood-brain barrier
maximum binding
cyclic adenosine 3’,5’-monophosphate
cyclic guanosine 3’,5’-monophosphate
choline acetyltransferase
central nervous system
cerebrospina1 fluid
dopamine P-hydroxylase
fluorescein isothiocyanate
insulin-like growth factor
intravenous
intraventricular
dissociation constant
mannose 6-phosphate
messenger ribonucleic acid
noradrenaline
neuropeptide Y
peptide histidine isoleucine
TRITC
TTR
T,
T4
VIP
5-HT
radioimmunoassay
sodium dodecyl sulphate polyacrylamide
gel electrophoresis
tetramethylrhodamine
isothiocyanate
transthyretin
triiodothyronine
thyroxine
vasoactive intestinal polypeptide
5-hydroxytryptamine
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