David Helfgott plays Rachmaninov Piano Concerto #3 (Copenhagen Philharmonic, 1995)

1. 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 • an anticholinergic for tardive dyskenesia. See also “Out of Tune”, written by Margaret Helfgott.

2. Bi/CNS 150: wrapping up This week: no quiz. Quiz-like credit for emailing Ralph or Henry a question for Friday’s session: What is a challenge for neuroscience in the remainder of the 21th Century? Give at least one reference from a journal (not a web site; not the text). Friday, December 4 Final exam posted, covers entire course, emphasizes 2nd half

3. Bi/CNS 150 Wednesday December 4, 2013 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 62

4. 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

5. Positive symptoms: Delusions, hallucinations, thought disorder Negative symptoms: Decreased motivation, diminished emotional expression Cognitive deficits: Impairments in attention, executive function, some types of memory 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 Motor abnormalities: Posturing, impaired coordination, “catatonia”

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

7. 2. Genetics (David Helfgott’s father; John Nash’s son) 100% identical twins 48% 17% fraternal twins children 50% siblings Concordance for Lifetime Risk of Schizophrenia parents shared DNA half siblings grandchildren 25% nephews/nieces uncles/aunts 1st cousins 12.5% 1% (~ independent of culture) general population 0% 10% 20% 30% 40% 50% Polygenic Genetically Multifactorial The disease occurs only if several genotypes are present together Several distinct genes (or sets of genotypes) can independently cause the disease Partially Penetrant Nongenetic or epigenetic factors are required, or the disease is inherently stochastic Like Figure 62-1

8. Clinical Neuroscience Molecular Neuroscience Human Genome and Associated Data

9. 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 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

10. 20% sequence A1 sequence B1 sequence B1 sequence A1 sequence B2 sequence A2 sequence A2 sequence B2 80% 40% 20% 60% 80% Hunting for Genes with SNPs, image 1 Controls Schizophrenics Locus A Chomosome 12 no linkage to schizophrenia 70% Locus B Chomosome 8 may be near a gene that helps to cause schizophrenia 30%

11. 20% sequence A1 sequence B1 sequence B1 sequence A1 sequence B2 sequence A2 sequence B2 sequence A2 80% 40% 20% 60% 80% recombination Hunting for Genes with SNPs, image Controls Schizophrenics Locus A Chomosome 12 no linkage to schizophrenia 70% Locus B Chomosome 8 may be near a gene that helps to cause schizophrenia 30%

12. Recent data suggested 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 characteristics have been very thoroughly assessed.

13. 37,000 cases, 113,00 controls 208 Authors, Nature, 2014 “Locus too broad” “Manhattan Plot” of Most Significant Loci CACNA1C, voltage-gated CA channel, α1C subunit “Timothy Syndrome”

14. Some identified genes (83 not previously reported): Many genes expressed in brain. Dopamine D2 receptor (GPCR), Metabotropic glutamate receptor 3 (Target of antipsychotic drugs) . Immune system. Glutamatergic transmission. Synaptic function and plasticity. Ca2+ channels. Other neuronal ion channels. Neuronal development. Partial overlap with autism and intellectual disability.

15. 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. epidermal growth factor A member of the neuregulin family. Neuregulin-1 is a transmembrane protein, proteolyzed to release a growth factor with EGF-like domain. Released fragment Released fragment #2 Cleavage #1

16. 3. Pathophysiology: Challenge of relating genetics to biology 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. 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

17. Unaffected twin Schizophrenic twin Increased size of cerebral ventricles Gross neuroanatomical abnormalities in schizophrenia (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. Figure 62-3 Decreased cortical gray matter (not shown here, Figure 62-2, 62-6) 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.

18. Cellular neuronal abnormalities in schizophrenia (not shown here) 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. Unaffected Subcellular neuronal abnormalities in schizophrenia Abnormal dendridic spines in prefrontal cortex- layer 3 Schizophrenic #1 Schizophrenic #2 (Figure 62-4)

19. 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

20. 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

21. 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)

22. 4. Objective physiological measurements that correlate with schizophrenia 1. Electroencephalograms 2. Eye pursuit (not discussed here)

23. Sensory gating anomaly measured electrophysiologically: Mouse data A, abnormal ratio N, normal ratio schizophrenic a (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. Patient data Freedman et al, PNAS, 1996

24. 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)

25. 6. Therapeutic approaches Clinical potency of “classical” or “typical” antipsychotic drugs correlates best with dopamine D2 receptor blocking dose (See Figure 62-7)

26. Regulators of G protein Signaling tune the kinetics of effector (GIRK channel) activation/deactivation receptor from Lecture 12 An effect of 5-HT in the hippocampus G protein membrane How far? Up to 1 m How fast? 10 s to days i q s t CHO CHO Activation of the 5-HT1A receptor on pyramidal cells hyperpolarizes the membrane, as does baclofen, an agonist of GABAB receptors. effector kinase channel enzyme Expressed: muscarinic ACh Receptor + GIRK . . . cytosol . . .+ RGS intracellular messenger Effects of both the 5-HT1A receptor and the GABAB receptor are blocked by pertussis toxin (PTX), which inactivates a class of G-proteins. The pathway from GPCR to gene activation cAMP Ca2+ RGS4 phosphorylated protein RGS nucleus GTP from Andrade and Chaput, 1991 Gαi We’ve discussed these three effects of Gi-coupled receptors GIRKs Decreased cAMP Gene activation

27. How do psychiatric drugs work? • “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.” • “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 Previous lecture

28. More modern approaches emphasize other transmitter systems, too Dopamine adjusts the volume— Blockedby antipsychotics Acetylcholine and GABA filter signal from noise Glutamate imprints new memories Robert Freedman

29. a9 The sensory gating anomaly maps near the α7 nicotinic acetylcholine receptor; No GWAS hit here (but it’s a messy region). 90% of schizophrenics smoke; α7 agonists and allosteric modulators are being tested for cognitive enhancement in schizophrenia. The α5-α3-β4 cluster also shows up in the GWAS study a10

30. Geoffrey Rush Plays David Helfgott in “Shine” (1997)

31. (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 Anjelica Huston Sydney Lassick

32. Conclusion: We know much more about schizophrenia than we knew a century ago. Some of the knowledge fits with hypotheses about either pathophysiology or therapeutic mechanisms End of Schizophrenia Lecture Bi/CNS 150