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

2. SLC6A4: 5’HTTLPR polymor- phism Cells: Serotonin signaling Systems: depression, anxiety disorders, neuroticism, response to SSRIs, substance abuse, hallucinations Behavior: complex functional interactions and emergent phenomena SLC6A4: How do we get there from here ?

3. Serotonin (5-HT) and Fear 5-HT strongly implicated in emotional behavior: 5-HT synapses targeted by mood-altering drugs 5-HT synapses targeted by mood-altering drugs SSRIs effective against panic, anxiety & depression SSRIs effective against panic, anxiety & depression 5-HT 1A partial agonists are effective anxiolytics 5-HT 1A partial agonists are effective anxiolytics 5-HT 1A knockout mice exhibit increased fear/anxiety 5-HT 1A knockout mice exhibit increased fear/anxiety 5-HTT 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: 5’HTTLPR polymor phism 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 SLC6A4: How do we get there from here ?

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 s allele carriers show a greater amygdala response than ll homozygous individuals p<.05 corrected first cohort n=14 second cohort n=14

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 survivalincreases cortical neuron survival sculpts glutamate innervation patternssculpts glutamate innervation patterns increases synaptic efficacy of glutamateincreases 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 associations: Alzheimers Disease, Parkinson’s Disease, bipolar disorder, schizophreniagenetic associations: Alzheimers Disease, Parkinson’s Disease, bipolar disorder, schizophrenia

11. The BDNF Gene 11p1411p13 CHROMOSOME 11 PROMOTER 5´5´ 1 29710401353 BP START CODON STOP CODON 681 468 492 G 492  A 492  Val 66  Met 66 MAY BE EXTRACELLULARLY ACTIVE AT TrkB RECEPTORS proBDNF (32 kDa) TRUNCATED proBDNF (28 kDa) SIGNAL PEPTIDE ACTIVITY UNKNOWN Val 66  Met 66 MATURE BDNF (14 kDa) SIGNAL PEPTIDE ESSENTIAL ROLE IN DEVELOPMENT, SURVIVAL AND FUNCTION OF NEURONS Val 66  Met 66 CLEAVED IN ENDOPLASMIC RETICULUM CLEAVED IN TRANS-GOLGI NETWORK AND/OR IMMATURE VESICLES OR

12. Intracellular trafficking of BDNF alleles in cultured hippocampal neurons Vector construct: Dendritic transport: BDNF met BDNF val Peri-nuclear packaging: BDNF val BDNF met GFPMAP2MERGED BDNFProGFP Val  Met

13. BDNF Secretion (pg/ml) Constitutive Secretion BDNF Secretion (pg/ml) Regulated Secretion Ctr +K + * vBDNFmBDNF BDNFProGFP Val  Met Egan et al Cell (2003) Differential secretion of BDNF alleles

14. BDNF: val66met polymor- phism Cells: Intracellular trafficking and regulated secretion Systems hippocampal processing of memory bipolar disorder, schizophrenia Alzheimer’s Disease, antidepressant effects Behavior: complex functional interactions and emergent phenomena BDNF: How do we get there from here ?

15. BDNF val 66 met genotype and episodic memory F(2,130)=5.04, P = 0.008

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

17. BDNF val 66 met 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 ε 4 carriers 3 apo ε 4 carriers

18. BDNF 66 met is associated with reduced 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, corrected

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. 25% 5% hippocampal activation during 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% 25% Variance in memory performance

21. Conclusion: BDNF val 66 met 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

22. CBDB/NIMH: Investigators Clinical genetics Michael Egan Terry Goldberg Thomas Hyde Lewellyn Bigelow Molecular genetics Bhashkar Kolachana Krishna Vakkalanka Rishi Balkissoon NICHD Masami Kojima Bai Lu fMRI/MRSI Joseph Callicott Venkatta Mattay Allesandro Bertolino Ahmad Hariri SPECT Andreas Heinz Douglas Jones

23. Genes, Cognition and Emotion: Conclusions 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. Genes Cells Systems Psychiatric syndromes Behavior

24. Genes, cognition and emotion: 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