Genes, Cognition

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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_at_nih.gov
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(No Transcript)
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• 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
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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
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COMT (catechol-O-methyltransferase)

• Catalyzing the transfer of a methyl group from
  S-adenosyl-L-methionin
  e to catechol

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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
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The COMT Gene
PROMOTER
PROMOTER
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COMT-MB START CODON
STOP CODON
TRANSMEMBRANE SEGMENT
PCR
COMT-S START CODON
5-GATGACCCTGGTGATAGTGG
5-CTCATCACCATCGAGATCAA
G1947 ? A1947 ? COMT-MB/S Val158/108 ?
Met158/108
high-activity thermo-stable ancestral allele
low-activity thermo-labile human allele
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Dopamine terminals in striatum and in prefrontal
cortex are not the same
Striatum
DA
DA transporter
DA receptor
COMT
Prefrontal cortex
NE transporter
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COMT and prefrontal dopamine A unique
relationship

• COMT accounts for more than 60 of DA degradation
  in PFC but lt15 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)

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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 in PFC
Systems
Behavior complex functional interactions and
emergent phenomena
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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)
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Cortical efficiency during working memory in
patients with early Parkinsons Disease Effect
of l-dopa
off state
10 patients stable performance
on state
SPM 99, plt.001
Mattay et al Ann Neurol 2002
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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
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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
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COMT genotype effects the efficiency of
information processing during working memory A
replication
vvgtvmgtmm, SPM 99, plt.005
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Effect of COMT genotype on executive cognition
n 218
n 181

n 58
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COMT val/met genotype and dopamine related
executive cognition in normal children
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Predicted effect of COMT genotype on the
prefrontal response to amphetamine
PD
vv - high activity low synaptic dopamine
mm low activity high synaptic dopamine
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Genotype, amphetamine, and memory load interact
in PFC The experimental model
2 back task
3 back task
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COMT val158met genotype,working memory load, and
response to amphetamine interact in PFC
plt.05 corrected
val/val
met/met
one back
two back
three back
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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.