Genes Cognition and Emotion Daniel R Weinberger M

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: 1. Why have genes for psychiatric disorders been hard to find? 2. 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: Cells: multiple Systems: subtle susceptibility abnormal molecular alleles information abnormalities each of processing small effect temperament Behavior: complex functional interactions and emergent phenomena

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

COMT: How do we get there from here ? COMT: val 158 met Cells: polymor-phism psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control, pain sensitivity… Systems: Behavior: complex functional interactions and emergent phenomena

The COMT Gene CHROMOSOME 22 1 PROMOTER 22 q 11. 23 22 q 11. 22 27 kb PROMOTER 5´ COMT-MB START CODON TRANSMEMBRANE SEGMENT COMT-S START CODON 210 BP 5´-CTCATCACCATCGAGATCAA Nla. III …CGTG… . . AGVKD. . high-activity thermo-stable ancestral allele STOP CODON PCR 5´-GATGACCCTGGTGATAGTGG Nla. III G 1947 A 1947 COMT-MB/S: Val 158/108 Met 158/108 Nla. III …CATG… . . AGMKD. . . low-activity thermo-labile human allele Nla. III

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

COMT and prefrontal dopamine A unique relationship… • COMT accounts for more than 60% of DA degradation in PFC but <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 e al 2002, Mazei et al 2002)

Dopamine signaling in prefrontal cortex: A cellular physiology of “efficient processing” Suboptimal D 1/D 2 -receptor signaling Optimal D 1? D 2 -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: Cells: val 158 met DA polymor- mediated phism 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 val 158 met genotype, working memory load, and response to amphetamine interact in PFC p<. 05 corrected val/val met/met one back two back three back

Cells: COMT: Systems: DA val 158 met Prefrontal polymorphm mediated excitability regulation of DA activity psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control… Behavior: complex functional interactions and emergent phenomena Conclusions: • COMT val 158/108 met 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.