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

3. 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

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

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

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

7. 1 27kb COMT-S START CODON COMT-MB START CODON TRANSMEMBRANE SEGMENT STOP CODON PROMOTER 5´5´ 22q11.22 22q11.23 CHROMOSOME 22 NlaIII 5´-GATGACCCTGGTGATAGTGG5´-CTCATCACCATCGAGATCAA 210 BP PCR … C A TG …..AG M KD... … C G TG ….. AG V KD.. high-activity thermo-stable ancestral allele low-activity thermo-labile human allele G 1947  A 1947  COMT-MB/S: Val 158/108  Met 158/108 The COMT Gene PROMOTER

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

9. 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 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 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) 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) minimal role of prefrontal dopamine transporters (Sesack et al 1998, Lewis et al 2001, Moron et al 2002, Mazei et al 2002)

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

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

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

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

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

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

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

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

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

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

20. one backtwo backthree back COMT val 158 met genotype,working memory load, and response to amphetamine interact in PFC val/val met/met p<.05 corrected

21. 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 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.COMT met/met individuals are at increased risk of an adverse brain response to amphetamine. COMT: val158met polymorphm Cells: DA mediated excitability Systems: Prefrontal regulation of DA activity psychosis, OCD, anxiety, drug abuse, bipolar disorder, aggression, impulse control… Behavior: complex functional interactions and emergent phenomena