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Imaging Gene Effects: in Search of Neurogenetic Mechanisms in Schizophrenia

Imaging Gene Effects: in Search of Neurogenetic Mechanisms in Schizophrenia. Karen Faith Berman, M.D. Section on Integrative Neuroimaging Clinical Brain Disorders Branch Genes, Cognition, & Psychosis Program National Institute of Mental Health Intramural Research Program, NIH, DHHS

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Imaging Gene Effects: in Search of Neurogenetic Mechanisms in Schizophrenia

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  1. Imaging Gene Effects:in Search of Neurogenetic Mechanisms in Schizophrenia Karen Faith Berman, M.D. Section on Integrative Neuroimaging Clinical Brain Disorders Branch Genes, Cognition, & Psychosis Program National Institute of Mental Health Intramural Research Program, NIH, DHHS karen.berman@nih.gov

  2. Brain dysfunction occurs at multiple levels of neuronal organization cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  3. Genes and Neuropsychiatric Illness: Why are they important? • Majority of risk for psychiatric illness is • related to inheritance • Genes clarify effects of the environment • Genes may identify at-risk individuals • Genes transcend phenomenological • diagnosis & represent mechanisms • of disease • Genes are entry points to molecular • pathways that may lead to • development of new treatments

  4. The Human Genome Sequence is Now Known (ca.2003) Nucleotides: 3 billion Genes: 30,000 Proteins: 600,000 • Variations in the • Genome: > 6 million • copy number vaiations: • CVNs) • single nucleotide • polymorphisms: SNPs

  5. Functional SNP (truncates protein) Single Nucleotide Polymorphisms: SNPs } single nucleotide polymorphism AATCC → AAGCC

  6. Complex (i.e.multifactorial) disorders like neuropsychiatric illness are polygenic and genetically heterogeneous affected person unaffected “nonpenetrant” From: Goldman et al Nat Rev Gen 2005

  7. The path from here to there… cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  8. Neuroimaging cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  9. Cellular Manifestations: DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation DLPFC Physiological Dysfunction: local & system-level Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  10. Prefrontal Function and Striatal DA Activity Are Inversely Related GLU prefrontal cortex GABA DOPAMINE striatum Pycock et al. 1980 Luillot et al. 1987 Jaskiw et al. 1988 Deutch et al. 1989 Kolachana et al. 1997 Saunders et al. 1998 Roberts et al. 1999 DA GABA DA brainstem

  11. DLPFC Pathophysiology and Striatal Dopamine Dysregulation Increased Striatal F-DOPA Ki in Patients DLPFC Hypofunction in Patients (Controls > Patients) P = 0.007, t-test P = 0.016, U test 0.011 0.010 Striatal Uptake (Occipital Reference Region) 0.009 Presynaptic Dopamine: 6-18F-DOPA 0.008 rCBF Oxygen-15 water CONTROLS PATIENTS Meyer-Lindenberg et al. Nature Neuroscience 2002

  12. DLPFC Pathophysiology Predicts Striatal Dopamine Dysregulation 60 60 55 Normalized R. DLPFC rCBF - WCST Normalized R. DLPFC rCBF - WCST 55 50 50 Rs = .37 p = .47 Rs = -.83 p = 0.04 .008 .010 .012 .008 .010 .012 Striatal Ki Striatal Ki CONTROLS PATIENTS Meyer-Lindenberg et al. Nature Neuroscience 2002 Meyer-Lindenberg et al. Nature Neuroscience 2002

  13. Genetic Mechanisms COMT, Sub-cortical DA, & DLPFC Patho-physiology Cellular Manifestations: DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation DLPFC Physiological Dysfunction: local & system-level Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  14. presynaptic Dopamine Transporter (reuptake) postsynaptic Two Mechanisms for Intrasynaptic Trafficking of Excess Dopamine COMT

  15. COMT mRNA expression in human brain: in situ hybridization DLPFC Striatum Matsumoto et al Neuroscience 2003 Catechol-O-methyl transferase (COMT) and dopamine trafficking in the synapse • COMT accounts for more than 60% of DA degradation in PFC,but <15% in striatum(Karoum et al 1994) • dopamine transporter has a minimal role in prefrontal synapses, but is abundant in striatum (Sesack et al 1998, Lewis et al 2001, Moron et al 2002, Mazei et al 2002) • COMT has primacy for dopamine trafficking in PFC. Allelic variability in COMT

  16. 22q11.23 22q11.22 CHROMOSOME 22 1 27kb …CATG… ..AGVKD.. ..AGMKD... The COMT val158/108met Polymorphism PROMOTER PROMOTER 5´ COMT-MB START CODON STOP CODON TRANSMEMBRANE SEGMENT COMT-S START CODON VALINE ALLELE “high-activity” thermo-stable ancestral allele G1947 A1947  COMT-MB/S: Val158/108 Met158/108 METHIONINE ALLELE “low-activity” thermo-labile human allele …CGTG… - Of interest in schizophrenia - Poorer executive cognition & working memory - Less efficient prefrontal physiology SOURCE: NCBI, GEN-BANK, ACCESSION # Z26491

  17. Dopamine Signaling in Prefrontal Cortex Suboptimal D1-receptor activity state Optimal D1-receptor activity state Adapted from Seamans et al. J Neurosci 2001 Dopamine biases pyramidal neurons to respond to sustained/consistent and not to transient excitatory inputs (i.e. DA focuses and stabilizes the response network)

  18. “Inverted U Dose-Response” Curve PD Supported by findings from several studies Arnsten and Goldman-Rakic, 1986, 1990 Arnsten et al., 1994 Murphy et al., 1994, 1996 a,b, 1997 Williams and Goldman-Rakic, 1995 Verma and Moghaddam, 1996 From Goldman-Rakic 2000

  19. ‘vv’ - high COMT activity low synaptic dopamine “mm’ – low COMT activity high synaptic dopamine ‘vm’ – intermediate Predicted effects ofCOMT genotype on prefrontal cortical function PD

  20. ‘vv’ - high COMT activity low synaptic dopamine “mm’ – low COMT activity high synaptic dopamine Predicted effects ofCOMT genotype on prefrontal cortical function with amphetamine PD

  21. Prefrontal Function and Striatal DA Activity Are Inversely Related COMTval GLU prefrontal cortex GABA DOPAMINE Pycock et al. 1980 Luillot et al. 1987 Jaskiw et al. 1988 Deutch et al. 1989 Kolachana et al. 1997 Saunders et al. 1998 Roberts et al. 1999 Bertolino et al. 2000, 2001 Meyer-Lindenberg et al. 2002 striatum DA GABA DA brainstem

  22. 51 yr old male, VAL/VAL 49 yr old male, VAL/MET COMT Genotype Affects Midbrain Dopamine in Postmortem Brain TH mRNA, Post-Mortem 2.0 1.6 1.2 TH mRNA Optical Density 0.8 0.4 0.0 Val / Met Val / Val COMT GENOTYPE Akil et al., J. Neurosci, 2003

  23. 18F FluoroDOPA, in vivo TH mRNA, Post-Mortem 2.0 Categ. Box & Whisker Plot: Midbrain Ki 0.0035 1.6 Midbrain Ki 1.2 TH mRNA Optical Density 0.0030 0.8 Prefrontal Cortical Activity 0.4 0.0025 0.0000 0.0 Met / Met Val / Met Val / Met Val / Val COMT GENOTYPE COMT GENOTYPE Akil et al., J. Neurosci, 2003 COMT Genotype Affects MidbrainDopamine in vivo Meyer et. al., Nature Neuroscience, 2005

  24. Midbrain FDOPA and PFC rCBFby COMT Genotype Relationship between midbrain FDOPA and PFC rCBF by COMT genotype Adjusted data fit the “Inverted U Dose-Response” curve directly From Goldman-Rakic 2000 Supported by findings from: Arnsten and Goldman-Rakic, 1986, 1990 Arnsten et al., 1994 Murphy et al., 1994, 1996 a,b, 1997 Williams and Goldman-Rakic, 1995 Verma and Moghaddam, 1996 Meyer Lindenberg et al. Nature Neuroscience, 2005

  25. Slifstein et al. Mol Psych, 2008 [11C]NNC 112 binding map Effect size for Val/Val compared with Met carriers. Abi-Dargham et al. J. Neurosci. 2002 COMT Genotype Also Affects D1 Dopamine Receptors

  26. rs165599 “Shifman et al” - 287 rs2097603 val/met rs4680 rs737865 “Shifman et al” rs 4633 rs 6269 M2 Rs4646310 hCV11804654* hCV2539283* hCV2538753* M3 rs2020917 1917bp 6218bp 8821bp 4706bp TXNRD2 5’ 5’ 3’ P1 P2 Exons1 2 3 4 5 6 val/met effect on COMTactivity -287 effect on COMT activity in met/met background val/val met/met Chen et al AJHG (2004) Bray et al AJHG 2003 The plot thickens genetically: multiple functional loci in COMT

  27. Lessons & Current Hot Topics • Haplotype effects • Gene-gene interactions • Gene-environment interactions Genes related to psychopathology are not about psychiatric diagnoses, per se. They are about the development and abnormal function of brain circuits related to the processing of cognitive and emotional information.

  28. Imaging Genetics and the Future of Neuropsychiatry • Where will imaging gene effects take us? • Greater appreciation of modifiable environmental triggers? • Primary prevention? • Outcome prediction? • New therapeutic targets?

  29. (Apud et al. Neuropsychopharmacol 2007; Apud & Weinberger NeuroRx 2006) NOVEL TREATMENTSTolcapone enhances DLPFC efficiency during working memory in schizophrenia THEN: COMT inhibitor previously used to augment Parkinson’s disease treament NOW: ?Cognitive/neurophysiological enhancement for schizophrenia?

  30. Genetic Mechanisms COMT, Sub-cortical DA, & DLPFC Patho-physiology Cellular Manifestations: DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation DLPFC Physiological Dysfunction: local & system-level Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory cognition psychiatric illness temperament Cells: subtle molecular abnormalities Genes: multiple susceptibility alleles each of small effect Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

  31. THANKS TO: NIMH INTRAMURAL RESEARCH PROGRAM Section on Integrative NeuroimagingZentralinstitut, Mannheim Philip Kohn Andreas Meyer-Lindenberg MD,PhD Shane Kippenhan, Ph.D. Mbemba Jabbi, Ph.D Clinical Brain Disorders Branch Katherine Roe, Ph.D. Daniel Weinberger, M.D. Tiffany Nash Bhaskar Kolachana, Ph.D Joel Bronstein Joel Kleinman, M.D., Ph.D. Deepak Sarpal Venkata Mattay, M.D. Dylan Wint, M.D. Joseph Callicott, M.D. Angela Ianni Jasmin Salloum, Ph.D. Joseph Masdeu, M.D. Daniel Eisenberg, M.D. NIH PET DEPARTMENT Peter Herscovitch, M.D. Richard Carson, Ph.D.

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