David Helfgott plays
Rachmaninov Piano Concerto #3
(Copenhagen Philharmonic, 1995)
as in the movie “Shine”
Born in Melbourne 1947
1962-1970 several schizoaffective
episodes
1966-70 Royal College of Music
1970-1980 Hospitalized in Australia
1984- present concert pianist
According to the biography by his wife (2000), his medication consisted of:
(1) chlorpromazine, a D2 receptor blocker for schizophrenia;
See Figures 60-6, 60-7, 60-9 and
(2) an anticholinergic for tardive dyskenesia.
See also “Out ofTune”, written by Margaret Helfgott.
1
Bi/CNS 150: wrapping up
Tonight, Wed 8 PM
Prof. Viviana Gradinaru presents a Watson Lecture on her research
Brain Control with Light
Beckman Auditorium
Friday, December 7 Final exam posted,
covers entire course, emphasizes 2nd half
Friday, December 14 Final exam due, 4:30 PM
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Bi/CNS 150
Wednesday December 5, 2012
Schizophrenia, a cognitive disorder
Lecture combines ideas of 4 academic research psychiatrists:
Eric Kandel, Columbia (our text)
Robert Freedman, Univ. Colo.
David Lewis, Univ. Pittsburgh
J. Michael McIntosh, Univ. of Utah
As dramatized by 3 movies:
Shine, A Beautiful Mind, One Flew Over the Cuckoo’s Nest
Kandel, Chapter 60
3
Schizophrenia.
1. Clinical description
2. Genetics
3. Pathophysiology: a century of failed ideas
4. Biomarkers and animal models
5. Heterozygote advantage: none known
6. Therapeutic approaches
4
1. Clinical description
The range of clinical features shows that schizophrenia affects multiple complex
brain systems
(Many simulated interviews appear on Youtube; HAL has a videotaped interview)
Prodromal signs: “he was weird, even as a child”
social isolation & withdrawal,
impairment in roles of normal function;
odd behavior & ideas; blunted affect; poor personal hygiene
Positive symptoms: Delusions, hallucinations, thought disorder
Negative symptoms: Decreased motivation, diminished emotional expression
Cognitive deficits: Impairments in attention, executive function,
some types of memory
Motor abnormalities: Posturing, impaired coordination, “catatonia”
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“He saw the world in a way no one could have imagined.”
6
2. Genetics
100%
(David Helfgott’s father; John Nash’s son)
identical twins
48%
17%
fraternal twins
children
50%
siblings
Concordance
for
Lifetime Risk
of
Schizophrenia
parents
shared DNA
half siblings
25%
grandchildren
nephews/nieces
uncles/aunts
12.5%
1st cousins
general population
1% (~ independent of culture)
0%
Several distinct genes
(or sets of genotypes)
can independently cause
the disease
10%
20%
Genetically
Multifactorial
Nongenetic or epigenetic factors
are required, or the disease is
inherently stochastic
30%
Polygenic
40%
50%
The disease occurs
only if several
genotypes are
present together
Partially
Penetrant
7
Molecular Neuroscience
Clinical Neuroscience
Human Genome
and
Associated Data
8
2009
3.1
1.0
We describe a map of 1.42 million single nucleotide polymorphisms (SNPs)
distributed throughout the human genome, providing an average density on
available sequence of one SNP every 1.9 kilobases. This high-density SNP
map provides a public resource for defining haplotype variation across the
genome, and should help to identify biomedically important genes for
diagnosis and therapy.
International HapMap project
A haplotype is a common pattern of
several nearby SNPs:
2 SNPs, but only 3 of 4 possible haplotypes exist
9
Hunting for Genes with SNPs, image 1
Controls
sequence A1
20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
Locus B
Chomosome 8
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
10
Hunting for Genes with SNPs, image
Controls
sequence A1
20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
recombination
Locus B
Chomosome 8
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
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8p21, site of recent schizophrenia linkages, including these genes:
neuregulin-1, frizzled-3, vesicular monoamine transporter-1,
calcineurin Aγ, early growth response-1
1 mm
Alberts 4-11
© Garland
12
Slide also appeared in a lecture on development of the NMJ,
“acetylcholine receptor-inducing activity”
ARIA (acetylcholine receptor-inducing activity),
first discovered at the neuromuscular junction, secreted by the nerve.
A member of the neuregulin family. Neuregulin-1 is a transmembrane protein,
proteolyzed to release a growth factor with EGF-like domain.
epidermal growth factor
Released
fragment
Released
fragment
Cleavage #1
#2
13
Recent data suggest that large deletions are associated with schizophrenia
Copy number variations
PLoS Genetics, Feb 2009
. . . common genetic variants, the focus of most research until recently, do not seem to have a
major impact on schizophrenia predisposition . . .
Very rare, large DNA deletions and duplications contribute to or explain a minority of
schizophrenia cases . . .
Although the small number of events identified here do not restrict focus to a finite set of
molecular pathways, we do show one event that deletes a gene known to interact with DISC1,
a gene known to cause psychiatric problems in one family. . .
Schizophrenia genetics research must turn sharply toward the identification of rare genetic
contributors . . .
The most important tool will be complete whole-genome sequencing of patients whose clinical
14
characteristics have been very thoroughly assessed.
3. Pathophysiology
thousands
Each “advance” in biology has been tried out on schizophrenia.
Early 20th century, German classification & Nazi genetics
1950’s American psychiatrists (including Bettelheim) reacted with “schizogenic mother”
or “refrigerator mother” hypothesis
1950, Linus Pauling fractionated urine; 1968 “Orthomolecular Psychiatry” in Science
1955, chlorpromazine  dopamine theories
Population of US Public Mental Insitutions
1970, glutamate theories
600
1995, growth factors, development, migration
500
2000, genetics & genomics
400
300
2003, interneuron diversity
200
2005, inflammation
100
There is no satisfactory explanation yet.
0
1800
1850
1900
1950
2000
2050
year
In general, modern theories of schizophrenia emphasize abnormal balance among
neuronal circuits or pathways, rather than individual neurons that either
(a) degenerate or
(b) fire too much or too little
15
Gross neuroanatomical abnormalities in schizophrenia
Increased size of cerebral ventricles
(lateral and 3rd) and
decreased brain volume is the
most replicated finding.
Ventricular enlargement is
found in affected twins of
monozygotic pairs discordant
for schizophrenia.
This enlargement appears to
be stable when patients are
followed up prospectively.
Unaffected twin
Figure 60-5
Schizophrenic twin
Decreased cortical gray matter (not shown here)
Especially evident in superior temporal gyrus, dorsal prefrontal cortex and limbic areas
such as the hippocampal formation and anterior cingulate cortex.
These abnormalities may be present in first-episode, never-medicated patients.
16
Cellular neuronal abnormalities in schizophrenia (not shown here)
Decreased numbers of neurons have been found in the hippocampus and the
dorsolateral prefrontal cortex.
In studies of monozygotic twins discordant for schizophrenia, there is diminished
activation of the dorsolateral prefrontal cortex as measured by SPECT and PET.
Unaffected
Subcellular neuronal
abnormalities in schizophrenia
Abnormal dendridic spines in
prefrontal cortex- layer 3
Schizophrenic #1
Schizophrenic #2
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Neuronal activity occurs during hallucinations
Specific neuronal circuits involving the
thalamus, caudate-putamen, anterior
cingulate, limbic cortex,
auditory cortex,
hippocampus and parahippocampal
gyrus are activated in schizophrenics
during auditory hallucinations.
Part of Figure 60-2
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Known activities of neuregulins (NRGs) fit with some pathophysiological
hypotheses about schizophrenia.
Theory 1. Schizophrenia results from a deficiency of glutamatergic innervation relative to
dopaminergic innervation.
NRG knockout mice display hyperactivity in behavioral tests similar to hyperactivity observed in
mice treated with the psychogenic drug phencyclidine (PCP) or with mutations that impair
glutamatergic neurotransmission or enhance dopaminergic neurotransmission. Treatment with
clozapine reversed the hyperactivity of these mice, and they had reduced levels of NMDA
receptors. Furthermore, application of soluble NRG1 to cultured neurons stimulates
transcription of NMDA receptors.
Theory 2. Abnormalities in glial biology contribute to the pathology of schizophrenia.
Neuregulins are required for initial differentiation of oligodendrocyte precursors and for their
survival. A variant of this idea is that a deficiency of glial growth factors––such as NRG––
predisposes to synaptic destabilization. It is clear that NRG signaling is required for the
stabilization of nerve-muscle synapses, and evidence for NRG involvement in astrocyte biology
might implicate neuregulins in formation or stabilization of central synapses.
Theory 3. Schizophrenia results from abnormalities in brain wiring.
Neuregulins regulate migration of neuronal precursors in culture.
Theory 4. Schizophrenia results from abnormalities in synaptic plasticity.
Neuregulin-1 inhibits induction of LTP.
D. L. Falls, Exp Cell Res, 2003
19
Nongenetic contributions: the other ~50%
(1) Nourishment and health of the fetus
Viral infections during pregnancy,
Possibly leading to low-level inflammation
(Prof. Paul Patterson, Caltech)
(2) Head injury
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4. Objective physiological measurements that correlate with schizophrenia
Biomarkers are objective, measurable biochemical, genetic, or other biological
indicators of a physiological or disease process. . . complex conditions, such as
mental illness, might benefit from constellations of several different biomarkers
being used in concert. . . biomarkers could facilitate definitive diagnosis of mental
disorders in individuals, assess the susceptibility of individuals to a particular
disorder, indicate changes in the severity of a disorder, and show the response of a
disorder to a given treatment. . .
Some disorders appear as a broad spectrum where signs and symptoms vary
enormously but yet collectively represent one general disorder (e.g. autism
spectrum disorders). In other instances, a particular symptom may appear across a
variety of mental disorders (e.g., cognitive impairment) or represent an
exaggeration of a dimension seen in healthy individuals (e.g., depressed mood). . .
Biomarkers could aid clinicians in categorizing particular signs and symptoms so
that a spectrum disorder could be broken down into well-defined subcategories,
allowing differential analysis or treatment.
Biomarkers . . . could be used in basic research to map the variability of a marker
across healthy populations.
(National Institute of Mental Health)
21
4. Objective physiological measurements that correlate with schizophrenia
1. Electroencephalograms
2. Eye pursuit (not discussed here)
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Sensory gating anomaly measured electrophysiologically:
C57/BL6 WT
100 V
100 ms
Voltage
Mouse data
Audio
(a) Observed in schizophrenics (~90%) but in only 8% of the general population
(b) Autosomal dominant transmission, even in healthy relatives of schizophrenics
(c) This trait maps to the vicinity of the α7 nicotinic receptor on chromosome 15.
A, abnormal ratio
schizophrenic
N, normal ratio
Patient data
a
Freedman et al, PNAS, 1996
23
5.
Heterozygote advantage: none known
Contrast with cystic fibrosis
(fluid retention may protect against dehydrating diseases)
Contrast with bipolar disorder
(hypomanic state may confer selective advantage)
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6. Therapeutic
approaches
Clinical potency of
“classical” or “typical”
antipsychotic drugs
correlates best
with
dopamine D2 receptor
blocking dose
(Nestler, 16-6)
25
We’ve discussed these three effects of Gi-coupled receptors
Regulators of G protein Signaling
tune the kinetics of effector (GIRK channel) activation/deactivation
CHO
CHO
GIRKs
Expressed: muscarinic ACh
Receptor +
GIRK . . .
Decreased cAMP
. . .+ RGS
RGS4
 
a
a
Gene activation
 
RGS
GTP
GTP
GDP + Pi
25
receptor
Gαi
An effect of 5-HT in the hippocampus
Activation of the 5-HT1A
receptor on pyramidal
cells hyperpolarizes the
membrane, as does
baclofen, an agonist of
GABAB receptors.
Effects of both the 5HT1A receptor and the
GABAB receptor are
blocked by pertussis
toxin (PTX), which
inactivates a class of Gproteins.
outside
from Lecture 12
G protein
i q s t
membrane
 
a
 
a
inside
effector
channel enzyme
intracellular
messenger
Ca2+ cAMP
The pathway from
GPCR to gene
activation
cytosol
kinase
phosphorylated
protein
nucleus
How fast?
10 s to days
How far?
Up to 1 m
26
How do psychiatric drugs work?
1. “The mood-elevating effects of fluoxetine [Prozac] are not evident after initial
exposure to the drug but require its continued use for several weeks. This delayed
effect suggests that it is not the inhibition of serotonin transporters per se, but some
adaptation to sustained increases in serotonin function that mediates the clinical
actions of fluoxetine. However, where these adaptations occur in the brain, and the
nature of the adaptations at the molecular level, have yet to be identified with
Previous lecture
certainty.”
2. “All current antipsychotic drugs exert their full therapeutic actions over weeks,
suggesting that, like lithium and antidepressants, slowly developing adaptations (in
this case to initial D2 dopamine receptor blockade) are required for their
antipsychotic effects.”
S. E. Hyman, E. Nestler, R. Malenka, 2008
Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition
27
More modern approaches emphasize other transmitter systems, too
Dopamine adjusts the
volume—
Blocked by
antipsychotics
Acetylcholine and GABA
filter signal from noise
Glutamate imprints new
memories
Robert Freedman
28
The sensory gating anomaly maps near the α7 nicotinic actylcholine receptor;
90% of schizophrenics smoke;
α7 agonists are being tested for cognitive enhancement in schizophrenia
a10
a9
29
30
(One Flew Over the Cuckoo’s Nest);
Novel by Ken Kesey
http://www.youtube.com/watch?v=B5NyyC-UjBM
Movie, 1975
Academy Awards:
Best picture (Michael Douglas, producer),
Best screenplay
Milos Forman (Best Director)
Jack Nicholson (McMurphy, Best Actor)
Louise Fletcher (Best Actress)
Other roles:
Danny DeVito
Sydney Lassick
31
Conclusion:
We know much more about schizophrenia than we knew a century ago,
But most of this knowledge is negative.
End of Schizophrenia Lecture
Bi/CNS 150
Henry Lester’s “office” hours Friday 1:15-2:00 Red Door
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Effector:
enzyme or channel
 
a
GTP
a
GDP + Pi
 
33
6. Therapeutic approaches
Clinical potency of “classical” or “typical” antipsychotic drugs correlates with dopamine
D2 receptor blocking dose (Figure 60-9) . . .
. . . . but modern “atypical” antipsychotics also block other GPCRs (Nestler, 16-8)
Haloperidol
Clozapine
Quetiapine
Affinity
D1 dopaminergic
D2 &D3 dopaminergic
Muscarinic cholinergic
5HT2A serotonergic
Risperidone
Olanzapine
Sertindole
α1 adrenergic
α2 adrenergic
H1 histaminergic
Terrible side effects
Conventionals:
tardive dyskinesia (mesostriatal pathway)
Atypicals:
weight gain
34