Adapted from Lesch & Mossner, Biol Psychiatry 44 1998

5’-HT transporter promoter polymorphism5’-HT transporter promoter polymorphism(5’-HTTLPR,17q11)(5’-HTTLPR,17q11)

(SLC6A4)(SLC6A4)

SLC6A4:5’HTTLPRpolymor-

phism

Cells:Serotonin signaling

Systems:

depression, anxiety disorders,

neuroticism, response to SSRIs, substance abuse,

hallucinations

Behavior:complex functional

interactions and emergent

phenomena

SLC6A4SLC6A4: How do we get there from here ?: How do we get there from here ?

Serotonin (5-HT) and FearSerotonin (5-HT) and Fear

5-HT strongly implicated in emotional 5-HT strongly implicated in emotional behavior:behavior:

• 5-HT synapses targeted by mood-altering drugs5-HT synapses targeted by mood-altering drugs• SSRIs effective against panic, anxiety & depressionSSRIs effective against panic, anxiety & depression

• 5-HT5-HT1A1A partial agonists are effective anxiolytics partial agonists are effective anxiolytics

• 5-HT5-HT1A1A knockout mice exhibit increased fear/anxiety knockout mice exhibit increased fear/anxiety

• 5-HTT knockout mice exhibit increased fear/anxiety5-HTT knockout mice exhibit increased fear/anxiety

Fear circuitry and the amygdala

Serotonin and the amygdala• 5-HT signaling and neuronal

excitability• 5-HTT knockout mice have

enhanced fear conditioning

SLC6A4:5’HTTLPRpolymorphism

Cells:serotonin mediated

excitability

Systems:amygdala

processing of fearful stimuli

depression, anxiety disorders,

neuroticism, response to SSRIs, substance abuse,

hallucinations

Behavior:complex functional

interactions and emergent phenomena

SLC6A4SLC6A4: How do we get there from here ?: How do we get there from here ?

Perceptual processing of fearful facesengages the amygdala

“match the emotion”

HypothesisHypothesis

The amygdala response during the perceptual processing of fearful stimuli will be greater in

s carriers than ll homozygotes

ll ls genotype

5’-HTTLPR genotype and fMRI during 5’-HTTLPR genotype and fMRI during perceptual processing of fearful facesperceptual processing of fearful faces

s allele carriers show a greater amygdala response than ll homozygous individuals

p<.05 correctedfirst cohort

n=14second cohort

n=14

Conclusion:5’-HTTLPR s allele carriers have reduced amygdala volumeand exaggerated amygdala excitation during perceptual processing of fearful stimuli, a likely mechanism of theirrelatively excessive fearfulness(and anxiety and neuroticism) and susceptibility for depression

ents

Brain Derived Neurotrophic Factor

and neuronal plasticity • increases cortical neuron survival increases cortical neuron survival • sculpts glutamate innervation patternssculpts glutamate innervation patterns• increases synaptic efficacy of glutamate increases synaptic efficacy of glutamate • modulates LTP in hippocampusmodulates LTP in hippocampus• expression increased during spatial memoryexpression increased during spatial memory• expression increased by antidepressant treatmentsexpression increased by antidepressant treatments• genetic associationsgenetic associations: Alzheimers Disease, : Alzheimers Disease,

Parkinson’s Disease, bipolar disorder, Parkinson’s Disease, bipolar disorder, schizophreniaschizophrenia

The BDNF Gene11p1411p13CHROMOSOME 11

PROMOTER

5´

1 297 1040 1353 BP

START CODON STOP CODON

681468492

G492 A492

Val66 Met66

MAY BE EXTRACELLULARLYACTIVE AT TrkB RECEPTORS

proBDNF (32 kDa)

TRUNCATED proBDNF (28 kDa)SIGNALPEPTIDE

ACTIVITY UNKNOWN

Val66 Met66

MATURE BDNF (14 kDa)SIGNALPEPTIDE

ESSENTIAL ROLE INDEVELOPMENT, SURVIVAL

AND FUNCTION OF NEURONS

Val66 Met66

CLEAVED IN ENDOPLASMIC RETICULUM

CLEAVED IN TRANS-GOLGI NETWORK

AND/OR IMMATURE VESICLESOR

Intracellular trafficking of BDNF alleles in Intracellular trafficking of BDNF alleles in cultured hippocampal neuronscultured hippocampal neurons

Vector construct:

Dendritic transport:

BDNF met

BDNF val

Peri-nuclear packaging:

BDNF val

BDNF met

GFP MAP2 MERGED

BDNFPro GFP

ValMet

0

6

12

18

BD

NF

Sec

retio

n (p

g/m

l) Constitutive Secretion

-5

5

15

25

35

BD

NF

Sec

retio

n (p

g/m

l)

Regulated Secretion

Ctr +K+ Ctr +K+

*

vBDNF mBDNF

BDNFPro GFP

ValMet

Egan et al Cell (2003)

Differential secretion of BDNF allelesDifferential secretion of BDNF alleles

BDNF:val66metpolymor-

phism

Cells:Intracellular trafficking

and regulated secretion

Systemshippocampal processing of

memory

bipolar disorder,schizophreniaAlzheimer’s

Disease, antidepressant

effects

Behavior:complex functional

interactions and emergent

phenomena

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

BDNF val66met genotype and episodic memory

WM

S-R

Lo

gic

al

Me

mo

ry I

I P

erc

en

tile

s

0

10

20

30

40

50

60

70

80

90

val/val val/met met/met

*

F(2,130)=5.04,P = 0.008

Incidental declarative memory engages Incidental declarative memory engages the hippocampusthe hippocampus

“New or Old?”

“Indoor or Outdoor?”

BDNF val66met genotype and hippocampal function during declarative memory

Subjects: 14 val/val individuals 14 met carriers (12 val/met)

6 females 6 females mean age: 30 age: 30

mean IQ: 110 ±1.5 IQ: 108 ±2.1 4 apo ε4 carriers 3 apo ε4 carriers

BDNF BDNF 6666metmet is associated with reduced is associated with reduced hippocampal engagement during memory processing hippocampal engagement during memory processing

Encoding

Retrieval

val/val (N=14) >val/met (N=14)

Groups matched for age, gender, IQ, education, apo ε4

SPM 99, p<.05, SPM 99, p<.05, correctedcorrected

What about behavior ?What about behavior ?• No significant group difference in reaction time during either encoding or recognition

• No significant group difference in accuracy during encoding (95% v. 93%, p>.2)

• But, significant group difference in accuracy during recognition

val group = 91.6% ± 1.5%

met group = 84.5% ± 2.6% F(1,26)=5.69, p<0.02

Hariri et al J Neurosci 2003

25%25%5%5%hippocampal

activationduring retrieval interaction of BDNF genotype

and hippocampal activation during encoding

BDNF val/met genotype, hippocampal activation and prediction of recognition

accuracy

variability of recall

5%5%25%25%

Variance in memory performanceVariance in memory performance

Conclusion:BDNF val66met genotype affects hippocampal neuronal function

and memory processing.

BDNF:Val66met Cells:

Intracellular trafficking

and regulated secretion

Systems:hippo-campal

processing

bipolar disorder,schizophrenia

Alzheimer’s Disease, antidepressant

effects

Behavior:complex

functional interactions and

emergent phenomena

CBDB/NIMH: InvestigatorsCBDB/NIMH: Investigators

Clinical geneticsMichael Egan Terry GoldbergThomas HydeLewellyn Bigelow

Molecular geneticsBhashkar Kolachana Krishna VakkalankaRishi Balkissoon

NICHDMasami KojimaBai Lu

fMRI/MRSIJoseph CallicottVenkatta MattayAllesandro BertolinoAhmad Hariri

SPECTAndreas HeinzDouglas Jones

Genes, Cognition and Emotion: Genes, Cognition and Emotion: ConclusionsConclusions

Genes that are weakly related to psychiatric syndromes are relatively strongly related to the

function of neural systems involved in processing cognitive and emotional information in brain.

GenesCells

Systems

Psychiatric syndromes

Behavior

Genes, cognition and emotion: Genes, cognition and emotion: Some Implications Some Implications

There are probably no genes for mental illness, per se, but rather genetic variations that impact on relevant information processing in brain.

Elaboration of the genetic architecture of processing in these circuits will revise concepts of mental disorders.

Elaboration of the molecular repercussions of genetic variations on these systems will identify causative/susceptibility mechanisms and new therapeutic targets.

Genes Cells Systems

Psychiatric syndromes

Behavior