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Genes, Cognition and Emotion

Genes, Cognition and Emotion. Daniel R. Weinberger, M.D. Genes, Cognition and Psychosis Program National Institute of Mental Health, NIH Bethesda, Maryland 20892 USA danielweinberger@nih.gov. Two Questions: Why have genes for psychiatric disorders been hard to find?

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Genes, Cognition and Emotion

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  1. Genes, Cognition and Emotion Daniel R. Weinberger, M.D. Genes, Cognition and Psychosis Program National Institute of Mental Health, NIH Bethesda, Maryland 20892 USA danielweinberger@nih.gov

  2. Two Questions: • Why have genes for psychiatric disorders been hard to find? • Why are genetic mechanisms of susceptibility so difficult to identify? One Answer: Genes do not encode psychiatric phenomena

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

  4. COMT (catechol-O-methyltransferase) • Catalyzing the transfer of a methyl group from S-adenosyl-L-methionine to catechol

  5. COMT: How do we get there from here ? psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control, pain sensitivity… COMT: val158met polymor-phism Behavior: complex functional interactions and emergent phenomena Cells: Systems:

  6. CHROMOSOME 22 22q11.23 22q11.22 27kb 1 210 BP NlaIII NlaIII NlaIII NlaIII NlaIII …CGTG… …CATG… ..AGMKD... ..AGVKD.. The COMT Gene PROMOTER PROMOTER 5´ COMT-MB START CODON STOP CODON TRANSMEMBRANE SEGMENT PCR COMT-S START CODON 5´-CTCATCACCATCGAGATCAA 5´-GATGACCCTGGTGATAGTGG G1947 A1947  COMT-MB/S: Val158/108 Met158/108 high-activity thermo-stable ancestral allele low-activity thermo-labile human allele

  7. Dopamine terminals in striatum and in prefrontal cortex are not the same Striatum DA DA transporter DA receptor COMT Prefrontal cortex NE transporter

  8. COMT and prefrontal dopamine A unique relationship… • COMT accounts for more than 60% of DA degradation in PFCbut <15% in striatum(Karoum et al 1994) • COMT knockout mice have increased prefrontal DA and enhanced memory(Gogos et al 1998; Houtari et al 2002; Kneavel et al 2000) • COMT inhibitors enhance working memory(Khromova et al 1995; Liljequist et al 1997) • minimal role of prefrontal dopamine transporters (Sesack et al 1998, Lewis et al 2001, Moron et al 2002, Mazei et al 2002)

  9. Dopamine signaling in prefrontal cortex: A cellular physiology of “efficient processing” Optimal D1?D2 -receptor signaling Suboptimal D1/D2-receptor signaling Adapted from: Seamans et al. J Neurosci 2001 DA focuses and stabilizes the representational network (i.e. it enhances signal-to-noise)

  10. Cortical “efficiency” during working memory in patients with early Parkinson’s Disease: Effect of l-dopa “off state” 10 patients stable performance “on state” SPM 99, p<.001 Mattay et al Ann Neurol 2002

  11. COMT: How do we get there from here ? psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control, pain sensitivity… COMT: val158met polymor- phism Cells: DA mediated excitability Systems: prefrontal information processing Behavior: complex functional interactions and emergent phenomena

  12. Predicted relative effects of COMT genotype on prefrontal cortical function ‘vv’ - high COMT activity low synaptic dopamine ‘mm’ – low activity high synaptic dopamine ‘vm’ – intermediate

  13. COMT genotype effects the efficiency of information processing during working memory: A replication vv>vm>mm, SPM 99, p<.005

  14. Effect of COMT genotype on executive cognition n = 218 n = 181 n = 58

  15. COMT val/met genotype and dopamine related executive cognition in normal children

  16. Predicted effect of COMT genotype on the prefrontal response to amphetamine PD ‘vv’ - high activity low synaptic dopamine ‘mm’ – low activity high synaptic dopamine

  17. Genotype, amphetamine, and memory load interact in PFC: The experimental model 2 back task 3 back task

  18. COMT val158met genotype,working memory load, and response to amphetamine interact in PFC p<.05 corrected val/val met/met one back two back three back

  19. psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control… Cells: DA mediated excitability COMT: val158met polymorphm Systems: Prefrontal regulation of DA activity Behavior: complex functional interactions and emergent phenomena • Conclusions: • COMT val158/108met genotype effects the efficiency (i.e. STN) of prefrontal cortical information processing, the likely mechanism by which COMT genotype is associated with psychopathology. • COMT met/met individuals are at increased risk of an adverse brain response to amphetamine.

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