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 Lack of 5-HT signaling (+ DA, NE) Not the whole story Most antidepressants Blocks serotonin transporter More serotonin signaling

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

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

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

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

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

BDNF mRNA & protein mRNA Protein Prefrontal cortex

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)

Vs wild type (+/+) Hippocampus Prefrontal cortex “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 I + IV = Ca dependent; IV = CRE site; IX = high amount of CpG sites, also in all mature mRNA sequences Prefrontal cortex

“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

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

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

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

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%

G x E

Serotonin transporter mutation Caspi 03

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

Human study Took blood samples and looked at leukocyte mRNA

I guess that’s it…. Thanks