Depression

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Depression
An affective disorder
“affect” means emotional state or
“mood”
• http://www.youtube.com/watch?v=JhlWdd
AXSRA
Nature 455:894 2008
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Treated by:
Electroconvulsive shock
Psychotherapy
Antidepressants
Animal models of depression
Deep brain stimulation of the Nucleus accumbens or the
subgenual cingulate cortex decreases depression
This is thought to inhibit the activity of these areas
BDNF is a neurotrophic factor that promotes neurogenesis,
growth of axon branches and dendrites, and
synaptogenesis
Depression is
associated
with increased
BDNF in N
accumbens
and VTA
The
Amygdala
processes
emotionally
stressful
stimuli
Stress (and depression)
lowers BDNF in the
hippocampus
Postmortem data from depressed
humans
A human polymorphism in the pro-domain of the BDNF
gene affects the packaging and release of BDNF & has
different effects on different aspects of depression
• Monoamine Hypothesis: Depression
results from a deficit in one or both of the
serotonin and norepinephrine diffuse
modulatory systems.
Serotonin and
Norepinephrine
modulatory systems
• Alternative: diathesis-stress hypothesis
• Diathesis means a predisposition to a
disease
• Activation of glucocorticoid receptors in
the hippocampus downregulates the
hypothalamic pituitary adrenal system.
• A lot of maternal care in rats upregulates
glucocorticoid receptors in hippocampus
• There is evidence that neurogenesis in the
hippocampus is important for mood
regulation.
• Stress-induced depression down-regulates
BDNF (brain-derived neurotropic factor)
expression and hence down regulates
neurogenesis.
• Antidepressants (imipramine)
upregulateBDNF expression
Stress-induced dimethylation
of chromatin surrounding
BDNF promoter decreases
expression.
Antidepressant-induced
acetylation upregulates
expression.
5-HT1b receptors and
depression
• 5-HT1b receptors are typically located on
the presynaptic terminals of either
serotonergic or other neurons.
• Activation of 5-HT1b receptors decreases
release of 5-HT.
• P11 interacts with 5-HT1b, but not other 5HT or Dopamine receptors in a yeast twohibrid assay
•
Fig. 1. Identification of an interaction between 5-HT1B receptors and p11.
(A) Results from a yeast two-hybrid screen showing an interaction of p11
with the 5-HT1B receptor (left; blue color), but not with an unrelated bait (C
115; right; no color), or with pRP21, 5-HT1A, 5-HT2A, 5-HT5A, 5-HT6, D1,
or D2 receptors. (B) Coimmunoprecipitation confirming that p11 interacts
with (left panel) V5 epitope–tagged 5-HT1B receptors in HeLa cells and with
(right panel) native 5-HT1B receptors in brain tissue from wild-type, but not
p11 KO, mice. The immunoprecipitates were analyzed by Western blotting
using a p11-specific antibody. The nonspecific band corresponds to the light
chains of the antibodies against V5 or 5-HT1B receptors ( -V5 and 5HT1B). (C) Immunofluorescence staining of p11 (left, red fluorescence), V5
epitope–tagged 5-HT1B receptors (middle, green fluorescence) and their
colocalization (right, yellow fluorescence) at the cell surface in HeLa cells.
(D) In situ hybridization made on coronal sections from a rat brain showing
that the distribution of p11 mRNA is similartothatof5-HT1B receptor mRNA
in (left to right) frontal cortex, ventromedial hypothalamus (arrow),
hippocampus (arrow), and raphe nuclei (arrow).
• Coimmunoprecipitation shows that P11
interacts with V5-tagged 5-HT1b receptors
in HeLa cells and in wildtype Mouse brain
(but not P11 knock-out brain).
• Immunocytochemical Colocalization of
P11 and 5-HT1b receptors in HeLa cells
• In situ hybridization showing similar
distribution of P11 and 5-HT1b mRNAs
Frontal cortex
Ventromedial
hypothalamus
Hippocampus
Raphe
Nuclei
• Regulation of P11 expression by
antidepressant treatments and in
depression like states.
The tricyclic antidepressant imipramine or electroconvulsive shock
upregulate P11 mRNA
• P11 mRNA was down-regulated in
“depressed” mice and human brains
Non-helpless mouse
Helpless Mouse
Human
• Fig. 2. Regulation of p11 expression by antidepressant
treatments and in depression-like states. In situ
hybridization illustrating an up-regulation of p11 mRNA in
the forebrain following (A) repeated treatment with
imipramine [10 mg/kg per day, intraperitoneally (i.p.) for
14 days] in mice (n = 8 per group) and (B)
electroconvulsive therapy (ECT) for 10 days in rats (n =
5 per group). Conversely, p11 mRNA was downregulated in (C) the forebrain in helpless H/Rouen versus
nonhelpless NH/Rouen mice (n = 10 per group) and (D)
in patients who suffered from unipolar major depression
(n = 15 per group). Data from the anterior (A; B; C, left;
D) and posterior (C, right) cingulate cortices were
normalized to the corresponding controls and represent
means ± SEM. *P < 0.05, ***P < 0.001 versus control by
Student's t test.
• Over expression of P11 in Cos-7 cells
increases the amount of 5-HT1b at the cell
surface
• Coexpression of P11 with 5-HT1b receptor
enhanced the ability of serotonin to
counteract the activation of adenyl cyclase
by forskolin
• Mice overexpressing P11 showed
behavioral changes similar to
antidepressant treatments: reduced
thigmotaxis or immobility in a tail
suspension test.
• P11 knockouts have depression-like
behavioral phenotypes:
• Increased thigmotaxis and tail-suspension
induced immobility
• Fig. 3. Biochemical and behavioral effects of overexpression of p11
in cells and in transgenic mice. (A) Biotinylation experiment from
COS-7 cells showing that p11 increases the amount of 5-HT1B
receptors at the cell surface. Data were normalized to the amount in
cells transfected only with 5-HT1B receptors and represent means ±
SEM for three experiments, each in triplicate. (B) The ability of
serotonin (10 µM) to counteract forskolin-induced cAMP formation in
COS-7 cells transfected with the 5-HT1B receptor is increased in the
presence of cotransfected p11. There was no significant difference
in the cAMP responses to forskolin with or without p11. Data are
normalized to forskolin-stimulated conditions, with or without p11,
and represent means ± SEM. Behavioral analysis on (C) thigmotaxis
and (D) the tail suspension test in transgenic mice overexpressing
p11 under the CamKII promoter. Black bars indicate mice with no
treatment and white bars doxycycline-treated mice. Data represent
means ± SEM for 10 to 18 mice per group. *P < 0.05, **P < 0.01
versus respective control by Student's t test.
P11 knockout results in less binding
by 5-HT1b ligands
• 5ht1b antagonist binding
• Goes down
P11KO reduces ability of 5HT
to down regulate a kinase
• P11 knockouts caused a loss of ability of
5-HT and the 5-HT1b agonist, anpirtoline
to downregulate ERK1/2 (Fig 4c) or to
decrease a PKA site phosphorylation (Fig
4D)
• 5-HT acting on 5-HT1b recptors in
terminals of cortical glutamatergic neurons
in the striatum reduced PSP amplitude in
wildtype, but very little in P11 knock-outs
• Since 5-HT1b receptors decrease 5-HT
turnover and P11 increases this decrease,
P11 knockouts increase this 5-HT turnover
(Fig 4F)
But 5-HT1b antagonist decreases
ultrasonic vocalization in the rat
Dawson et al O6
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