David Helfgott plays Rachmaninov Piano Concerto 3 Copenhagen

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 D 2 receptor blocker for schizophrenia; See Figures 60 -6, 60 -7, 60 -9 and (2) an anticholinergic for tardive dyskenesia. See also “Out of. Tune”, 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 2 nd half Friday, December 14 Final exam due, 4: 30 PM 2

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 Mc. Intosh, 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” 5

“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 children 50% siblings Concordance for Lifetime Risk of Schizophrenia parents shared DNA half siblings 25% grandchildren nephews/nieces uncles/aunts 12. 5% 48% 17% fraternal twins 1 st 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 Hap. Map 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 A 1 20% Schizophrenics 20% sequence A 1 Locus A Chomosome 12 sequence A 2 no linkage to schizophrenia 80% 40% 70% Locus B Chomosome 8 sequence B 1 may be near a gene that helps to cause schizophrenia sequence B 2 60% 30% 10

Hunting for Genes with SNPs, image Controls sequence A 1 20% Schizophrenics 20% sequence A 1 Locus A Chomosome 12 sequence A 2 no linkage to schizophrenia 80% 40% 70% recombination Locus B Chomosome 8 sequence B 1 may be near a gene that helps to cause schizophrenia sequence B 2 60% 30% 11

8 p 21, 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 Cleavage #1 #2 Released fragment 13

Recent data suggest that large deletions are associated with schizophrenia Copy number variations PLo. S 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 DISC 1, 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. 14

3. Pathophysiology Each “advance” in biology has been tried out on schizophrenia. Early 20 th 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. 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 3 rd) 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 17

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 18

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 NRG 1 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 20

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) 22

Sensory gating anomaly measured electrophysiologically: Mouse 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 α 7 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) 24

6. Therapeutic approaches Clinical potency of “classical” or “typical” antipsychotic drugs correlates best with dopamine D 2 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 GIRKs Expressed: muscarinic ACh Receptor + GIRK. . . Decreased c. AMP . . . + RGS 4 Gene activation RGS GTP from Lecture 12 receptor Gαi G protein i q s t An effect of 5 -HT in the hippocampus Activation of the 5 -HT 1 A receptor on pyramidal cells hyperpolarizes the membrane, as does baclofen, an agonist of GABAB receptors. Effects of both the 5 HT 1 A receptor and the GABAB receptor are blocked by pertussis toxin (PTX), which inactivates a class of Gproteins. membrane effector channel enzyme The pathway from GPCR to gene activation intracellular messenger Ca 2+ c. AMP 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 D 2 dopamine receptor blockade) are required for their antipsychotic effects. ” S. E. Hyman, E. Nestler, R. Malenka, 2008 Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2 nd 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 α 7 nicotinic actylcholine receptor; 90% of schizophrenics smoke; α 7 agonists are being tested for cognitive enhancement in schizophrenia a 10 a 9 29

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(One Flew Over the Cuckoo’s Nest); Novel by Ken Kesey http: //www. youtube. com/watch? v=B 5 Nyy. C-Uj. BM Movie, 1975 Academy Awards: Best picture (Michael Douglas, producer), Best screenplay Milos Forman (Best Director) Jack Nicholson (Mc. Murphy, Best Actor) Louise Fletcher (Best Actress) Other roles: Danny De. Vito 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 32

Effector: enzyme or channel b g a GTP a GDP + Pi b g 33

6. Therapeutic approaches Clinical potency of “classical” or “typical” antipsychotic drugs correlates with dopamine D 2 receptor blocking dose (Figure 60 -9). . . . but modern “atypical” antipsychotics also block other GPCRs (Nestler, 16 -8) Haloperidol Clozapine Quetiapine Affinity D 1 dopaminergic D 2 &D 3 dopaminergic Muscarinic cholinergic 5 HT 2 A serotonergic Risperidone Olanzapine Sertindole α 1 adrenergic α 2 adrenergic H 1 histaminergic Terrible side effects Conventionals: tardive dyskinesia (mesostriatal pathway) Atypicals: weight gain 34