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