Download Weinberger, MD

Genes, Cognition
and Emotion
Daniel R. Weinberger, M.D.
Genes, Cognition and Psychosis Program
National Institute of Mental Health, NIH
Bethesda, Maryland 20892 USA
[email protected]
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
The Wisconsin Card Sorting Task
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)
 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
polymorphism
Cells:
Systems:
Behavior:
complex functional
interactions and
emergent
phenomena
The COMT Gene
CHROMOSOME 22
1
PROMOTER
22q11.23
22q11.22
27kb
PROMOTER
5´
COMT-MB START CODON
TRANSMEMBRANE SEGMENT
COMT-S START CODON
210 BP
5´-CTCATCACCATCGAGATCAA
NlaIII
…CGTG…
..AGVKD..
high-activity
thermo-stable
ancestral allele
STOP CODON
PCR
5´-GATGACCCTGGTGATAGTGG
NlaIII
NlaIII
G1947  A1947

COMT-MB/S:
Val158/108
 Met158/108
NlaIII
…CATG…
..AGMKD...
low-activity
thermo-labile
human allele
NlaIII
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
et al 2002, Mazei et al 2002)
Dopamine signaling in prefrontal cortex:
A cellular physiology of “efficient processing”
Suboptimal D1/D2-receptor signaling
Optimal 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:
Cells:
val158met
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
Perseverative Errors (t-scores)
WCST
60
55
50
45
40
35
30
vv
vm
COMT Genotype
mm
n = 218
sibs
n = 181
n = 58
patients
controls
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
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0.4
% SIGNAL CHANGE (3-Back)
0.4
% SIGNAL CHANGE (2-Back)
% SIGNAL CHANGE (1-Back)
p<.05
corrected
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0
PLA
DEX
one back
0.4
0.35
0.3
val/val
0.25
0.2
0.15
0.1
0.05
0
PLA
DEX
two back
PLA
DEX
three back
met/met
Cells:
COMT:
Systems:
DA
val158met
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 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.