1 / 24

Adapted from Lesch & Mossner, Biol Psychiatry 44 1998

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

sinclair
Télécharger la présentation

Adapted from Lesch & Mossner, Biol Psychiatry 44 1998

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 5’-HT transporter promoter polymorphism (5’-HTTLPR,17q11) (SLC6A4) Adapted from Lesch & Mossner, Biol Psychiatry 44 1998

  2. 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

  3. 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

  4. Fear circuitry and the amygdala • Serotonin and the amygdala • 5-HT signaling and neuronal • excitability • 5-HTT knockout mice have • enhanced fear conditioning

  5. 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

  6. Perceptual processing of fearful faces engages the amygdala “match the emotion”

  7. Hypothesis The amygdala response during the perceptual processing of fearful stimuli will be greater in s carriers than ll homozygotes ll ls genotype

  8. 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

  9. 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

  10. 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

  11. 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 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

  12. 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

  13. 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)

  14. 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

  15. BDNF val66met genotype and episodic memory F(2,130)=5.04, P = 0.008

  16. Incidental declarative memory engages the hippocampus “Indoor or Outdoor?” “New or Old?”

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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.

  22. 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

  23. 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.

  24. 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.

More Related