The tryptophan hydroxylase 2 (Tph2) polymorphism C2432T mediates mRNA expression and responses to antidepressant treatment in a sex‐specific manner

Abstract

The mechanisms behind successful treatment response in Major Depressive Disorder remain unclear. We examined whether a novel single nucleotide polymorphism (SNP) C2432T in the Tph2 gene mediates differences in response to SSRIs between two mouse strains: MRL/MpJ (MRL; SSRI‐responding, T/T) versus C57Bl/6J (C57; SSRI‐nonresponding, C/C) (Balu et al, 2009). We cross‐bred the MRL and C57 strains to isolate C2432T in the F2 generation and determined functionality using the response to SSRIs in the tail suspension test (TST). F2 T/T females showed an enhanced citalopram response (p<0.001, n=10), while males showed no genotype‐specific effects. The C2432T SNP also mediated Tph2 mRNA expression, with T/T animals showing increased expression in the midbrain (p<0.05, n=11–16). However, in response to chronic SSRI treatment, there was no difference by genotype in F2 generation animals in measures of hippocampal neurogenesis or novelty‐induced hypophagia behavior. The C2432T SNP may mediate serotonin involvement to acute antidepressant response in a sex‐specific manner, but did not mediate the effects of chronic antidepressant treatment.