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
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. Stop 5HTT action with drug
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 PFC more sensitive Don’t know SERT levels mRNA
Hippocampus
Prefrontal cortex

7. Post-translational cleavage
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 (+/+) 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

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

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

16. 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%

17. G x E

18. Serotonin transporter mutation
Caspi 03

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

20. Human study
Took blood samples and looked at leukocyte mRNA

21. I guess that’s it….
Thanks