Genes, Cognition Genes, Cognition and Emotion and Emotion

Daniel R. Weinberger, M.D.

Genes, Cognition and Psychosis Program National Institute of Mental Health, NIH

Bethesda, Maryland 20892 USAdanielweinberger@nih.gov

Two Questions: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

Genes:multiple

susceptibility alleles each of

small effect

Cells:subtle

molecular abnormalities

Systems:abnormal

information processing

behavioralphenotypes

Behavior:complex functional

interactions and emergent

phenomena

The path from here to there…

The Wisconsin Card Sorting Task

temperament

cognition

COMT (catechol-O-methyltransferase) Catalyzing the transfer of a methyl group from

S-adenosyl-L-methionine to catechol

COMT:val158met polymor-

phism

Cells: Systems:

psychosis, OCD, anxiety,drug abuse,

bipolar disorder,aggression,

impulse control,pain sensitivity…

Behavior:complex functional

interactions and emergent

phenomena

COMTCOMT: How do we get there from here ?: How do we get there from here ?

1 27kb

COMT-S START CODON

COMT-MB START CODONTRANSMEMBRANE SEGMENT

STOP CODON

PROMOTER

5´

22q11.2222q11.23CHROMOSOME 22

NlaIIINlaIII NlaIIINlaIIINlaIII

5´-GATGACCCTGGTGATAGTGG5´-CTCATCACCATCGAGATCAA210 BP

PCR

…CATG…

..AGMKD...

…CGTG…

..AGVKD..

high-activitythermo-stableancestral allele

low-activitythermo-labilehuman allele

G1947 A1947

COMT-MB/S:

Val158/108 Met158/108

The COMT GeneThe COMT Gene

PROMOTER

Dopamine terminals in striatum and in Dopamine terminals in striatum and in prefrontal cortex are not the sameprefrontal cortex are not the same

StriatumStriatum

Prefrontal cortexPrefrontal cortex

DADA

DA transporterDA transporter

DA receptorDA receptor

COMTCOMT

NE transporterNE transporter

COMT and prefrontal dopamineCOMT and prefrontal dopamineA unique relationship…A unique relationship…

•COMT accounts for more than 60% of DA COMT accounts for more than 60% of DA degradation in PFCdegradation in PFC but <15% in striatumbut <15% in striatum (Karoum et al 1994)(Karoum et al 1994)

•COMT knockout mice have increased COMT knockout mice have increased prefrontal DA and prefrontal DA and enhanced memoryenhanced memory (Gogos et (Gogos et

al 1998; Houtari et al 2002; Kneavel et al 2000)al 1998; Houtari et al 2002; Kneavel et al 2000)

• COMT inhibitors enhance working memoryCOMT inhibitors enhance working memory (Khromova et al 1995; Liljequist et al 1997)(Khromova et al 1995; Liljequist et al 1997)

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

Adapted from: Seamans et al. J Neurosci 2001

Dopamine signaling in prefrontal cortex:Dopamine signaling in prefrontal cortex:A cellular physiology of “efficient processing”A cellular physiology of “efficient processing”

Optimal D1?D2 -receptor signalingSuboptimal D1/D2-receptor signaling

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”

“on state”

SPM 99, p<.001SPM 99, p<.001

10 patients10 patientsstable performancestable performance

Mattay et al Ann Neurol 2002

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

COMTCOMT: How do we get there from here ?: How do we get there from here ?

‘vv’ - high COMT activitylow synaptic dopamine

‘vm’ – intermediate

‘mm’ – low activityhigh synaptic dopamine

Predicted relative effects of COMT Predicted relative effects of COMT genotype on prefrontal cortical functiongenotype on prefrontal cortical function

COMT genotype effects the efficiency of COMT genotype effects the efficiency of information processing during working information processing during working

memory: A replicationmemory: A replication

vv>vm>mm, SPM 99, p<.005

Effect of COMT genotype on executive cognitionEffect of COMT genotype on executive cognition

sibs

patients

controls

COMT Genotype

WC

ST

Per

seve

rati

ve E

rro

rs (

t-sc

ore

s)

30

35

40

45

50

55

60

v v v m m m

n = 218

n = 181n = 58

COMT val/met genotype and dopamine related executive cognition in

normal children

PD

Predicted effect of COMT genotype on thePredicted effect of COMT genotype on the

prefrontal response to prefrontal response to amphetamineamphetamine

‘vv’ - high activitylow synaptic dopamine

‘mm’ – low activityhigh synaptic dopamine

Genotype, amphetamine, and memory load Genotype, amphetamine, and memory load interact in PFC: The experimental modelinteract in PFC: The experimental model

2 back task 3 back task

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

PLA DEX

% S

IGN

AL

CH

AN

GE

(2

-Bac

k)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

PLA DEX

% S

IGN

AL

CH

AN

GE

(3

-Ba

ck

)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

PLA DEX

% S

IGN

AL

CH

AN

GE

(1

-Ba

ck

)

one back two back three back

COMT COMT valval158158metmet genotype,working memory load, and genotype,working memory load, and response to amphetamine interact in PFCresponse to amphetamine interact in PFC

val/val

met/met

p<.05corrected

Conclusions:• COMT COMT valval158/108158/108metmet genotype effects the genotype effects the efficiency (i.e. STN) of prefrontal cortical efficiency (i.e. STN) of prefrontal cortical information processing, the likely mechanism by information processing, the likely mechanism by which COMT genotype is associated with which COMT genotype is associated with psychopathology. psychopathology. •COMT COMT met/met met/met individuals are at increased risk individuals are at increased risk of an adverse brain response to amphetamine.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