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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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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
polymor-
phism
Cells:
Serotonin signaling
Systems:
Behavior:
complex functional interactions and emergent phenomena
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
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
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 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
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
SIGNAL
PEPTIDE
TRUNCATED proBDNF (28 kDa)
ACTIVITY UNKNOWN
The BDNF Gene
11p13
11p14
CHROMOSOME 11
297
681
1040
1353 BP
1
468
PROMOTER
492
5´
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
BDNF
GFP
Intracellular trafficking of BDNF alleles in cultured hippocampal neurons
ValMet
Vector construct:
GFP
MAP2
MERGED
BDNF val
Dendritic transport:
BDNF met
BDNF val
Peri-nuclear
packaging:
BDNF met
BDNF
GFP
Differential secretion of BDNF alleles
Constitutive Secretion
ValMet
BDNF Secretion (pg/ml)
vBDNF
mBDNF
Regulated Secretion
*
BDNF Secretion (pg/ml)
Ctr +K+
Ctr +K+
Egan et al Cell (2003)
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
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 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
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
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
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.
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
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.
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.
