Serotonin disruption at gestation alters expression of genes associated with serotonin synthesis and reuptake at weaning

FABIO, M. C.; SERVIN-BERNAL, I. J. C.; DEGANO, A. L.; PAUTASSI, R. M.

PSYCHOPHARMACOLOGY

SPRINGER

Año: 2022

0033-3158

Rationale: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seem to exert long term consequences, including altered anxiety responses and problematic use of alcohol. Objective: we analyzed, in mice, the effects of transient 5-HT depletion at gestation, (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes, that may serve as a proxy for autistic- or anxiety-like phenotypes. Methods: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies and ethanol’s anti-anxiety effects, at postnatal days (P)21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real time RT-PCR. Dopamine 2 Receptor (D2R) expression was also analyzed via RT-PCR in order to further explore possible effects of PCPA on dopaminergic transmission. Results: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behavior were observed. Conclusion: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.