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bioRxiv · 10.1101/2023.11.30.569458

Alterations of adult prefrontal circuits induced by early postnatal fluoxetine treatment mediated by 5-HT7 receptors.

De Stasi, A. M.·de San Martin, J. Z.·Soto, N. N.·Aguirre, A.·Olusakin, J.·Lourenco, J.·Gaspar, P.·Bacci, A.
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Abstract

The prefrontal cortex (PFC) plays a key role in high-level cognitive functions and emotional behaviors, and PFC alterations correlate with different brain disorders including major depression and anxiety. In mice, the first two postnatal weeks represent a critical period of high sensitivity to environmental changes. In this temporal window, serotonin (5- HT) levels regulate the wiring of PFC cortical neurons. Early life insults and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affect PFC development leading to depressive and anxiety-like phenotypes in adult mice. However, the mechanisms responsible for these dysfunctions remain obscure. We found that postnatal FLX exposure (PNFLX) results in reduced overall firing, and high-frequency bursting of putative pyramidal neurons (PNs) of deep layers of the medial PFC (mPFC) of adult mice in vivo. Ex-vivo, patch-clamp recordings revealed that PNFLX abolished high-frequency firing in a distinct subpopulation of deep-layer mPFC PNs, which transiently express the serotonin transporter SERT. SERT+ and SERT- PNs exhibit distinct morpho-functional properties. Genetic deletion of 5-HT7Rs prevented the PNFLX-induced reduction of PN firing in vivo and pharmacological 5-HT7R blockade precluded altered firing of SERT+ PNs in vitro. This indicates a pivotal role of this 5-HTR subtype in mediating 5-HT-dependent maturation of PFC circuits that are susceptible to early-life insults. Overall, our results suggest potential novel neurobiological mechanisms, underlying detrimental neurodevelopmental consequences induced by early-life alterations of 5-HT levels.

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De Stasi, A. M., de San Martin, J. Z., Soto, N. N., Aguirre, A., Olusakin, J., Lourenco, J., Gaspar, P., Bacci, A.. 2023-12-03. Alterations of adult prefrontal circuits induced by early postnatal fluoxetine treatment mediated by 5-HT7 receptors.. https://doi.org/10.1101/2023.11.30.569458

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