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David Helfgott playsRachmaninov 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.

Friday, December 13 Final exam due, 4:30 PM

Bi/CNS 150: wrapping up

Thursday December 5Review session, here (Broad 100 ** 6:30 M**)

Friday, December 6 PS 6 due 11 AM

Final exam posted, covers entire course, emphasizes 2nd half

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Bi/CNS 150

Wednesday December 4, 2013

Schizophrenia, a cognitive disorder

Kandel, Chapter 62

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

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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

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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)

Motor abnormalities: Posturing, impaired coordination, “catatonia”

Negative symptoms: Decreased motivation, diminished emotional expression

Cognitive deficits: Impairments in attention, executive function, some types of memory

Positive symptoms: Delusions, hallucinations, thought disorder

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

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“He saw the world in a way no one could have imagined.”

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general population

1st cousins

uncles/aunts

nephews/nieces

grandchildren

half siblings

parents

siblings

children

fraternal twins

identical twins

shared DNA

100%

50%

25%

12.5%

Concordance for

Lifetime Risk of

Schizophrenia

0% 10% 20% 30% 40% 50%

48%17%

1% (~ independent of culture)

Genetically Multifactorial

Several distinct genes (or sets of genotypes)

can independently cause the disease

The disease occurs only if several genotypes are

present together

Polygenic

Nongenetic or epigenetic factors are required, or the disease is

inherently stochastic

PartiallyPenetrant

2. Genetics (David Helfgott’s father; John Nash’s son)

Like Figure 62-1

8

Molecular Neuroscience Clinical Neuroscience

Human Genomeand

Associated Data

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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

3.1 1.0

A haplotype is a common pattern of several nearby SNPs:

2 SNPs, but only 3 of 4 possible haplotypes exist

2009

10

20%

80%

60%

40%

20%

80%

30%

70%

Locus AChomosome 12

no linkage toschizophrenia

Locus BChomosome 8

may be near a gene that helps to cause

schizophrenia

sequence A1

sequence A2

sequence A1

sequence A2

Controls Schizophrenics

sequence B1

sequence B2

sequence B1

sequence B2

Hunting for Genes with SNPs, image 1

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20%

80%

60%

40%

20%

80%

30%

70%

Locus AChomosome 12

no linkage toschizophrenia

Locus BChomosome 8

may be near a gene that helps to cause

schizophrenia

sequence A1

sequence A2

sequence A1

sequence A2

Controls Schizophrenics

sequence B1

sequence B2

sequence B1

sequence B2

recombination

Hunting for Genes with SNPs, image

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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

Alberts 4-11© Garland

1 m

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ARIA (acetylcholine receptor-inducing activity),first discovered at the neuromuscular junction, secreted by the nerve.

Cleavage #1 #2

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

Slide also appeared in a lecture on development of the NMJ, “acetylcholine receptor-inducing activity”

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Recent data suggest that large deletions are associated with schizophrenia

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 characteristics have been very thoroughly assessed.

Copy number variations

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Population of US Public Mental Insitutions

0

100

200

300

400

500

600

1800 1850 1900 1950 2000 2050

yearth

ousa

nds

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

1970, glutamate theories

1995, growth factors, development, migration

2000, genetics & genomics

2003, interneuron diversity

2005, inflammation

There is no satisfactory explanation yet.

3. Pathophysiology

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

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Gross neuroanatomical abnormalities in schizophrenia

Decreased cortical gray matter (not shown here, Figure 62-2, 62-6)

Unaffected twin Schizophrenic twin

Increased size of cerebral ventricles

Figure 62-3

(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.

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.

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Modestly 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.

Cellular neuronal abnormalities in schizophrenia (not shown here)

Abnormal dendridic spines in prefrontal cortex- layer 3

Subcellular neuronal abnormalities in schizophrenia

Unaffected

Schizophrenic #1

Schizophrenic #2

(Figure 62-4)

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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.

Neuronal activity occurs during hallucinations

Part of Figure 60-2

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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

Known activities of neuregulins (NRGs) fit with some pathophysiological hypotheses about schizophrenia.

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(1) Nourishment and health of the fetus

Viral infections during pregnancy,

Possibly leading to low-level inflammation

(Prof. Paul Patterson, Caltech)

(2) Head injury

Nongenetic contributions: the other ~50%

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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)

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1. Electroencephalograms

2. Eye pursuit (not discussed here)

4. Objective physiological measurements that correlate with schizophrenia

100 ms

100 VC57/BL6 WT

Voltage

Audio

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Sensory gating anomaly measured electrophysiologically:

A, abnormal ratio

N, normal ratio

schizophrenic

Freedman et al, PNAS, 1996

Mouse data

Patient data

(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.

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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)

Clinical potency of

“classical” or “typical”

antipsychotic drugs

correlates best

with

dopamine D2 receptor blocking dose

(See Figure 62-7)

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6. Therapeutic approaches

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RGS4

Gαi

GTP

Regulators of G protein Signaling tune the kinetics of effector (GIRK channel) activation/deactivation

Expressed: muscarinic ACh Receptor + GIRK . . .

. . .+ RGS

CHO CHO

25GTP GDP + Pi

RGS

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 5-HT1A receptor and the GABAB receptor are blocked by pertussis toxin (PTX), which inactivates a class of G-proteins.

We’ve discussed these three effects of Gi-coupled receptors

cytosol

The pathway from GPCR to gene

activation

nucleus

How fast?10 s to days

How far?Up to 1 m

kinase

phosphorylatedprotein

cAMPCa2+

intracellular

messenger

receptor

tsqiG protein

enzymechannel effector

membrane

from Lecture 12 outside

inside

outside

inside

GIRKs

Decreased cAMP

Gene activation

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 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, 2008Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition

How do psychiatric drugs work?

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Previous lecture

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Dopamine adjusts the volume—

Blocked by antipsychotics

Acetylcholine and GABA filter signal from noise

Glutamate imprints new memories

More modern approaches emphasize other transmitter systems, too

Robert Freedman

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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.

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Movie, 1975Academy Awards:Best picture (Michael Douglas, producer), Best screenplayMilos Forman (Best Director)Jack Nicholson (McMurphy, Best Actor)Louise Fletcher (Best Actress)Other roles:Danny DeVitoAnjelica HustonSydney Lassick

(One Flew Over the Cuckoo’s Nest);Novel by Ken Kesey

http://www.youtube.com/watch?v=B5NyyC-UjBM

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End of Schizophrenia LectureBi/CNS 150

Conclusion:

We know much more about schizophrenia than we knew a century ago,

But most of this knowledge is negative.

Henry Lester’s “office” hours Friday 1:15-2:00 Red Door