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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 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? • Why are genetic mechanisms of susceptibility so difficult to identify? One Answer: Genes do not encode psychiatric phenomena
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
COMT (catechol-O-methyltransferase) • Catalyzing the transfer of a methyl group from S-adenosyl-L-methionine to catechol
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:
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
Dopamine terminals in striatum and in prefrontal cortex are not the same Striatum DA DA transporter DA receptor COMT Prefrontal cortex NE transporter
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)
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)
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
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
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
COMT genotype effects the efficiency of information processing during working memory: A replication vv>vm>mm, SPM 99, p<.005
Effect of COMT genotype on executive cognition n = 218 n = 181 n = 58
COMT val/met genotype and dopamine related executive cognition in normal children
Predicted effect of COMT genotype on the prefrontal response to amphetamine PD ‘vv’ - high activity low synaptic dopamine ‘mm’ – low activity high synaptic dopamine
Genotype, amphetamine, and memory load interact in PFC: The experimental model 2 back task 3 back task
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
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.