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5’-HT transporter promoter polymorphism (5’-HTTLPR,17q11). (SLC6A4). Adapted from Lesch & Mossner, Biol Psychiatry 44 1998. SLC6A4 : How do we get there from here ?. depression, anxiety disorders, neuroticism, response to SSRIs, substance abuse, hallucinations. SLC6A4: 5’HTTLPR

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slide1

5’-HT transporter promoter polymorphism

(5’-HTTLPR,17q11)

(SLC6A4)

Adapted from Lesch & Mossner, Biol Psychiatry 44 1998

slide2

SLC6A4: How do we get there from here ?

depression,

anxiety disorders,

neuroticism,

response to SSRIs,

substance abuse,

hallucinations

SLC6A4:

5’HTTLPR

polymor-

phism

Cells:

Serotonin signaling

Systems:

Behavior:

complex functional interactions and emergent phenomena

serotonin 5 ht and fear

Serotonin (5-HT) and Fear

5-HT strongly implicated in emotional behavior:

5-HT synapses targeted by mood-altering drugs

SSRIs effective against panic, anxiety & depression

5-HT1A partial agonists are effective anxiolytics

5-HT1A knockout mice exhibit increased fear/anxiety

5-HTT knockout mice exhibit increased fear/anxiety

fear circuitry and the amygdala

Fear circuitry and the amygdala

  • Serotonin and the amygdala
    • 5-HT signaling and neuronal
    • excitability
    • 5-HTT knockout mice have
    • enhanced fear conditioning
slide5

SLC6A4: How do we get there from here ?

depression,

anxiety disorders,

neuroticism,

response to SSRIs,

substance abuse,

hallucinations

SLC6A4:

5’HTTLPR

polymor

phism

Cells:

serotonin mediated excitability

Systems:

amygdala processing of fearful stimuli

Behavior:

complex functional interactions and emergent phenomena

slide6

Perceptual processing of fearful faces

engages the amygdala

“match the emotion”

hypothesis

Hypothesis

The amygdala response during the perceptual processing of fearful stimuli will be greater in s carriers than ll homozygotes

ll

ls genotype

slide8

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

first cohort

n=14

second cohort

n=14

p<.05 corrected

s allele carriers show a greater amygdala response than

ll homozygous individuals

slide9

Conclusion:

5’-HTTLPR s allele carriers

have reduced amygdala volume

and exaggerated amygdala

excitation during perceptual

processing of fearful stimuli,

a likely mechanism of their

relatively excessive fearfulness

(and anxiety and neuroticism)

and susceptibility for depression

ents

b rain d erived n eurotrophic f actor and neuronal plasticity
Brain Derived Neurotrophic Factor and neuronal plasticity
  • increases cortical neuron survival
  • sculpts glutamate innervation patterns
  • increases synaptic efficacy of glutamate
  • modulates LTP in hippocampus
  • expression increased during spatial memory
  • expression increased by antidepressant treatments
  • genetic associations: Alzheimers Disease, Parkinson’s Disease, bipolar disorder, schizophrenia
slide11

Val66 Met66

SIGNAL

PEPTIDE

TRUNCATED proBDNF (28 kDa)

ACTIVITY UNKNOWN

The BDNF Gene

11p13

11p14

CHROMOSOME 11

297

681

1040

1353 BP

1

468

PROMOTER

492

G492 A492

Val66 Met66

STOP CODON

START CODON

proBDNF (32 kDa)

MAY BE EXTRACELLULARLY

ACTIVE AT TrkB RECEPTORS

CLEAVED IN TRANS-GOLGI

NETWORK

AND/OR IMMATURE VESICLES

CLEAVED IN ENDOPLASMIC RETICULUM

OR

Val66 Met66

SIGNAL

PEPTIDE

MATURE BDNF (14 kDa)

ESSENTIAL ROLE IN

DEVELOPMENT, SURVIVAL

AND FUNCTION OF NEURONS

slide12

Pro

BDNF

GFP

Intracellular trafficking of BDNF alleles in cultured hippocampal neurons

ValMet

Vector construct:

GFP

MAP2

MERGED

BDNF val

Dendritic transport:

BDNF met

BDNF val

Peri-nuclear

packaging:

BDNF met

slide13

Pro

BDNF

GFP

Differential secretion of BDNF alleles

Constitutive Secretion

ValMet

BDNF Secretion (pg/ml)

vBDNF

mBDNF

Regulated Secretion

*

BDNF Secretion (pg/ml)

Ctr +K+

Ctr +K+

Egan et al Cell (2003)

slide14

BDNF: How do we get there from here ?

bipolar disorder,

schizophrenia

Alzheimer’s

Disease,

antidepressant

effects

BDNF:

val66met

polymor-phism

Cells:

Intracellular trafficking and regulated secretion

Behavior:

complex functional interactions and emergent phenomena

Systems

hippocampal processing of memory

slide16

Incidental declarative memory engages

the hippocampus

“Indoor or Outdoor?”

“New or Old?”

bdnf val 66 met genotype and hippocampal function during declarative memory

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

slide18

BDNF 66met is associated with reduced

hippocampal engagement during memory processing

val/val (N=14)

>

val/met (N=14)

Groups matched for age,

gender, IQ, education, apo ε4

Encoding

SPM 99, p<.05, corrected

Retrieval

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

slide20

BDNF val/met genotype, hippocampal

activation and prediction of recognition accuracy

Variance in memory performance

variability of recall

5%

25%

25%

hippocampal activation

during retrieval

5%

interaction of BDNF genotype

and hippocampal activation

during encoding

slide21

bipolar disorder,

schizophrenia

Alzheimer’s Disease,

antidepressant

effects

BDNF:

Val66met

Systems:

hippo-

campal processing

Cells:

Intracellular trafficking and regulated secretion

Behavior:

complex functional interactions and emergent phenomena

Conclusion:

BDNF val66met genotype affects

hippocampal neuronal function

and memory processing.

slide22

CBDB/NIMH: Investigators

Clinical genetics

Michael Egan

Terry Goldberg

Thomas Hyde

Lewellyn Bigelow

Molecular genetics

Bhashkar Kolachana

Krishna Vakkalanka

Rishi Balkissoon

fMRI/MRSI

Joseph Callicott

Venkatta Mattay

Allesandro Bertolino

Ahmad Hariri

SPECT

Andreas Heinz

Douglas Jones

NICHD

Masami Kojima

Bai Lu

slide23

Genes, Cognition and Emotion: Conclusions

Psychiatric

syndromes

Genes

Cells

Behavior

Systems

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.

slide24

Genes, cognition and emotion:

Some Implications

Psychiatric

syndromes

Genes

Behavior

Cells

Systems

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.