Bi/CNS 150
David Helfgott,
Copenhagen Philharmonic,
1995
(as in movie “Shine”)
Wednesday
December 3, 2013
Schizophrenia
Bruce Cohen
August Strindberg, self-portrait 1891
Kandel, Chapter 62
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Case History of David Helfgott
•Born in Melbourne 1947
•1962-1970 several schizoaffective
episodes
•1966-70 Royal College of Music
•1970-1980 Hospitalized in Australia
•1984- present concert pianist
•1996 biographical drama Shine based
on life of Helfgott
David Helfgott playing
Rachmaninov Piano Concerto #3
(Copenhagen Philharmonic, 1995)
According to the biography by his wife (2000), his medication was:
(1) chlorpromazine, a D2 receptor blocker for schizophrenia
(2) an anticholinergic for tardive dyskinesia.
2
What is schizophrenia?
• “Schizophrenia is a thought disorder, characterized by illogical
thinking, lack of reasoning, and inability to recognize reality”
from Meyer and Quenzer, Psychopharmacology, 2012
• Disturbances in perception (hallucinations) common, particularly
auditory hallucinations such as hearing commanding or insulting
voices
• Delusions (beliefs not based on reality) also common
• Speech can be disturbed (ungrammatical, vague, confused,
repetitive)
• Inappropriate or absent emotional responses (blunted affect)
3
Clinical Signs of Schizophrenia
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 signs: delusions, hallucinations, thought disorder (relieved by
D2 antagonists)
Negative signs: decreased motivation (avolition), diminished emotional
expression, social withdrawal, anhedoinia
Cognitive signs: impairments in attention, executive function,
some types of memory (negative and cognitive symptoms resistant to
antipsychotic drug treatment)
Motor abnormalities: Posturing, impaired coordination, “catatonia”
4
Genetic risk of schizophrenia
100%
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
Similar to Kandel, Figure 62-1
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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, only 3 of 4 possible haplotypes exist
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Hunting for Genes with SNPs
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%
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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
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Large deletions associated with schizophrenia
PLoS Genetics, Feb 2009
•Very rare, large DNA deletions and duplications contribute to or explain a minority of
schizophrenia cases . . .
•One event deletes a gene known to interact with DISC1, a gene known to cause psychiatric
problems in one family
•DISC1 stands for “Disrupted in Schizophrenia 1”
•DISC1 defect is linked to bipolar/schizophrenia phenotype in 80% of large Scottish family
•DISC1 protein appears to regulate a variety of developmental and mitochondrial process
CNVs are copy number variations
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Anatomical correlates of schizophrenia
Increased size of cerebral ventricles
•Increased lateral and 3rd
ventricle volume, and
decreased grey matter is
highly replicated finding
•Ventricular enlargement is
found in affected twinsof
monozygotic pairs discordant
for schizophrenia.
•This enlargement appears to
be stable when patients are
followed up prospectively.
Unaffected twin
Figure 62-3
Schizophrenic twin
Decreased cortical gray matter (not shown here, Figure 62-2, 62-6)
Evident in superior temporal gyrus, dorsal prefrontal cortex and limbic areas such as the
hippocampus and anterior cingulate cortex.
These abnormalities can be found in never-medicated patients.
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Histological correlates of schizophrenia
•
Schizophrenia associated with modest reductions in number of neurons in
hippocampus and 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.
Subcellular neuronal
abnormalities in schizophrenia
Reduction in dendridic spines
in prefrontal cortex- layer 3
compared to unaffected
individuals
Unaffected
Schizophrenic #1
Schizophrenic #2
(Kandel, Figure 62-4)
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Neuronal activity during hallucinations
Neuro-imaging shows neuronal circuits
involving the thalamus, caudateputamen, anterior cingulate, limbic
cortex,
auditory cortex,
hippocampus and parahippocampal
gyrus are activated in schizophrenics
during auditory hallucinations.
Part of Kandel, Figure 60-2
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Nongenetic risk factors for schizophrenia
•
Nourishment and health of the fetus (study of
Dutch children born during Nazi occupation)
•
Maternal viral infection during pregnancy
(late Prof. Paul Patterson, Caltech)
•
Traumatic head injury
13
Endophenotypes (intermediate phenotypes)
for schizophrenia
1. Sensory gating (habituation) deficit
2. Eye pursuit deficits
3. Deficits in working memory
14
Auditory gating measured electrophysiologically in hippocampus (CA3 layer)
C57/BL6 WT
100 V
100 ms
Voltage
Mouse
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
response ratio
schizophrenic
Human
a
N, normal
response ratio
Freedman et al, PNAS, 1996
15
Therapeutic
approaches
Effective clinical dose
of “classical” or
“typical” antipsychotic
drugs correlates best
with binding affinity for
dopamine D2 receptor
(See Figure 62-7)
16
Hospitalization of schizophrenics
Population of US Public Mental Insitutions
600
thousands
500
400
300
200
100
0
1800
1850
1900
1950
2000
2050
year
1955, chlorpromazine
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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
18
How do antipsychotic drugs work?
“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
19
The sensory gating anomaly maps near the α7 nicotinic acetylcholine
receptor;
90% of schizophrenics smoke;
α7 agonists and allosteric modulators are being tested for cognitive
enhancement in schizophrenia.
a10
a9
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End of Schizophrenia Lecture
Bi/CNS 150
Bruce Cohen’s office hours, Wednesday 1:15-2:00 328 Kerchhoff
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