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1 Bi/CNS 150 Wednesday December 3, 2013 Schizophrenia Bruce Cohen Kandel, Chapter 62 August Strindberg, self-portrait 1891 David Helfgott, Copenhagen Philharmonic,

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Presentation on theme: "1 Bi/CNS 150 Wednesday December 3, 2013 Schizophrenia Bruce Cohen Kandel, Chapter 62 August Strindberg, self-portrait 1891 David Helfgott, Copenhagen Philharmonic,"— Presentation transcript:

1 1 Bi/CNS 150 Wednesday December 3, 2013 Schizophrenia Bruce Cohen Kandel, Chapter 62 August Strindberg, self-portrait 1891 David Helfgott, Copenhagen Philharmonic, 1995 (as in movie “Shine”)

2 2 David Helfgott playing Rachmaninov Piano Concerto #3 (Copenhagen Philharmonic, 1995) 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 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. Case History of David Helfgott

3 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

4 4 Clinical Signs of Schizophrenia Motor abnormalities: Posturing, impaired coordination, “catatonia” 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) Positive signs: delusions, hallucinations, thought disorder (relieved by D2 antagonists) 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

5 5 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 Nongenetic or epigenetic factors are required, or the disease is inherently stochastic Partially Penetrant Genetic risk of schizophrenia Similar to Kandel, Figure 62-1 The disease occurs only if several genotypes are present together Polygenic

6 6 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, only 3 of 4 possible haplotypes exist 2009

7 7 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

8 8 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

9 9 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

10 10 Anatomical correlates of 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 Increased lateral and 3 rd 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. 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.

11 11 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. Histological correlates of schizophrenia Reduction in dendridic spines in prefrontal cortex- layer 3 compared to unaffected individuals Subcellular neuronal abnormalities in schizophrenia Unaffected Schizophrenic #1 Schizophrenic #2 (Kandel, Figure 62-4)

12 12 Neuro-imaging shows 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 during hallucinations Part of Kandel, Figure 60-2

13 13 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 Nongenetic risk factors for schizophrenia

14 14 1. Sensory gating (habituation) deficit 2.Eye pursuit deficits 3.Deficits in working memory Endophenotypes (intermediate phenotypes) for schizophrenia

15 15 Auditory gating measured electrophysiologically in hippocampus (CA3 layer)  A, abnormal response ratio N, normal response ratio schizophrenic Freedman et al, PNAS, 1996 Mouse Human (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.

16 Effective clinical dose of “classical” or “typical” antipsychotic drugs correlates best with binding affinity for dopamine D2 receptor (See Figure 62-7) 16 Therapeutic approaches

17 17 1955, chlorpromazine Hospitalization of schizophrenics

18 18 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 Three effects of G i -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

19 “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 antipsychotic drugs work? 19

20 20   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.

21 21 End of Schizophrenia Lecture Bi/CNS 150 Bruce Cohen’s office hours, Wednesday 1:15-2:00 328 Kerchhoff

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