1. 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 (2)an anticholinergic for tardive dyskenesia. See also “Out ofTune”, written by Margaret Helfgott.

2. Friday, December 13 Final exam due, 4:30 PM Bi/CNS 150: wrapping up Thursday December 5 Review session, here (Broad 100 ** 6:30 M**) Friday, December 6 PS 6 due 11 AM Final exam posted, covers entire course, emphasizes 2 nd half

3. 3 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

4. 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. 5 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

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

7. 7 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 Partially Penetrant 2. Genetics (David Helfgott’s father; John Nash’s son) Like Figure 62-1

8. 8 Molecular Neuroscience Clinical Neuroscience Human Genome and Associated Data

9. 9 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. 10 20% 80% 60% 40% 20% 80% 30% 70% Locus A Chomosome 12 no linkage to schizophrenia Locus B Chomosome 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

11. 11 20% 80% 60% 40% 20% 80% 30% 70% Locus A Chomosome 12 no linkage to schizophrenia Locus B Chomosome 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

12. 12 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

13. 13 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 Slide also appeared in a lecture on development of the NMJ, “acetylcholine receptor-inducing activity”

14. 14 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

15. 15 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. 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

16. 16 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.

17. 17 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)

18. 18 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

19. 19 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.

20. 20 (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%

21. 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. 22 1. Electroencephalograms 2. Eye pursuit (not discussed here) 4. Objective physiological measurements that correlate with schizophrenia

23. 23 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.

24. 24 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)

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

26. 26 RGS4 GαiGαi GTP Regulators of G protein Signaling tune the kinetics of effector (GIRK channel) activation/deactivation Expressed: muscarinic ACh Receptor + GIRK......+ RGS CHO RGS An effect of 5-HT in the hippocampus Activation of the 5-HT 1A receptor on pyramidal cells hyperpolarizes the membrane, as does baclofen, an agonist of GABA B receptors. Effects of both the 5- HT 1A receptor and the GABA B receptor are blocked by pertussis toxin (PTX), which inactivates a class of G- proteins. from Andrade and Chaput, 1991 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 phosphorylated protein cAMP Ca 2+ intracellular messenger receptor tsqi G protein enzymechannel effector membrane from Lecture 12 GIRKs Decreased cAMP Gene activation

27. 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, 2008 Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition How do psychiatric drugs work? 27 Previous lecture

28. 28 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

29. 29   The sensory gating anomaly maps near the α 7 nicotinic acetylcholine receptor; 90% of schizophrenics smoke; α7 agonists and allosteric modulators are being tested for cognitive enhancement in schizophrenia.

30. 30

31. 31 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 (One Flew Over the Cuckoo’s Nest); Novel by Ken Kesey http://www.youtube.com/watch?v=B5NyyC-UjBM

32. 32 End of Schizophrenia Lecture Bi/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