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Serotonin transporter effect on BDNF

Serotonin transporter effect on BDNF. “Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans”. Serotonin & depression. Depression Lack of 5-HT signaling (+ DA, NE) Not the whole story Most antidepressants.

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Serotonin transporter effect on BDNF

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  1. Serotonin transporter effect on BDNF “Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans”

  2. Serotonin & depression • Depression • Lack of 5-HT signaling (+ DA, NE) • Not the whole story • Most antidepressants Blocks serotonin transporter More serotonin signaling

  3. Today’s Rats • Serotonin receptor knockout model • SERT or 5-HTT • Back to genetics 101 • +/+ wild type • +/- hetrozygote (only 1 good copy) • -/- KO

  4. But wait… Stop 5HTT action with drug Stop depression Stop 5HTT action with KO Induce depression

  5. BDNF & depression • In the prefrontal cortex (PFC) & hippocampus • More BDNF is a good thing

  6. BDNF mRNA – Exon IX mRNA • PFC more sensitive • Don’t know SERT levels Hippocampus Prefrontal cortex

  7. BDNF mRNA & protein mRNA Protein Hippocampus mBDNF ProBDNF mRNA Exon XI Post-translational cleavage translation

  8. BDNF mRNA & protein mRNA Protein Prefrontal cortex

  9. Exons of BDNF cAMP Responsive Element (CRE) High CpG count contains coding region for mature BDNF protein (Roth 09) Activity dependent more Ca2+, more transcription (Roth 09) CaMKII, MEKK, CRE (Tian 09) (Takeuchi 02)

  10. Vs wild type (+/+) “We have analyzed the expression of transcripts containing exons IV and VI since, up to date, their promoters have been well characterized.” Hippocampus cAMP Responsive Element (CRE) Activity dependent more Ca2+, more transcription CaMKII, MEKK, PKA Prefrontal cortex

  11. “The reduction of BDNF expression observed in SERT mutant rats might be due to the lack of the transporter during the entire life, encompassing development as well as adulthood. To discriminate between these possibilities, we have used a pharmacological strategy and we investigated the neurotrophin expression in the prefrontal cortex after subchronic (21 days) treatment of adult 5-HTT+/+ and 5-HTT−/− rats with fluoxetine, a selective-serotonin reuptake inhibitor. ” Not significant

  12. Both used a 5HTT blocker…. but at different times Vogel 1990 Molteni 2010? 1 4 8 11 Week Neonate Adulthood? Cassano 2006

  13. Vogel 1990 Molteni 2010 Clomipramine treatment Fluoxitine treatment @ neonate @ adult Hippocampal BDNF PFC BDNF (Cassano 2006) Looks like depression Looks healthy

  14. Growth arrest and DNA-damage-inducible, beta (Gadd45β) • Demethylates CpGs on DNA (activates gene) • Shown to affect BDNF

  15. Serotonin transporter mutation(humans) • “5HTT gene-linked polymorphic region” (5-HTTLPR) • Long (l) and short (s) alleles • Short copy has reduced 5HTT transcription • Rates • l/l - 31% • l/s - 51% • s/s - 17%

  16. G x E

  17. Serotonin transporter mutation Caspi 03

  18. Long (l) form • Two forms of this allele • La & Lg • Lg produces similar 5HTT levels as the S form

  19. Human study • Took blood samples and looked at leukocyte mRNA

  20. I guess that’s it…. Thanks

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