Abstract
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 seems 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 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 behaviors 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.
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Acknowledgements
The authors would like to thank Dr. Gabriela Paglini who kindly lends us the D2R primer.
Funding
This work was supported by grants from the Agencia Nacional de Promoción Científica y Técnica (FONCYT 2018–00597) and Universidad Nacional de Córdoba (SECyT-UNC). This work was also supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, Argentina).
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Fabio, M.C., Servin-Bernal, I.J.C., Degano, A.L. et al. Serotonin disruption at gestation alters expression of genes associated with serotonin synthesis and reuptake at weaning. Psychopharmacology 239, 3355–3366 (2022). https://doi.org/10.1007/s00213-022-06228-z
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DOI: https://doi.org/10.1007/s00213-022-06228-z