Serotonin Modulates the Maturation of the Medial Prefrontal Cortex and Hippocampus: Relevance to the Etiology of Emotional and Cognitive Behaviors

Increasing evidence suggests that anxiety and depression disorders have neurodevelopmental roots, with a strong case for early-life serotonergic dysfunction in their ontogeny. For instance, disrupting serotonergic tone during critical developmental periods results in dysregulated adult affective behaviors, in mice. However, insight into the mechanism by which early-life serotonin levels impact emotional behaviors in later-life, remains scarce. Based on its potent neurotrophic properties, we hypothesized that serotonin acts during development to guide the maturation of brain regions implicated in the modulation of both the emotional and cognitive features of anxiety and depression disorders, namely the medial prefrontal cortex (mPFC) and hippocampus (HC). To address this hypothesis, we employed a pharmacological mouse model in which serotonin levels were increased using a selective serotonin reuptake inhibitor, fluoxetine (FLX), during a previously established critical post-natal time window (post-natal day 2-11; "PN-FLX" mouse model). The effect of this post-natal serotonergic disruption on the structural, physiological and functional properties of the adult mPFC and HC was assessed. In the mPFC, we found morphological and electrophysiological changes specific to cortical layer 2/3. Pyramidal neurons in layer 2/3 of the infralimbic (IL) sub-region of the mPFC, displayed decreased dendritic arborization, concomitant with reduced intrinsic excitability. Conversely, prelimbic (PL) layer 2/3 neurons displayed normal dendritic arborization, but increased intrinsic excitability. Together, these changes produce a reduced IL/PL output ratio. In order to probe the functional consequences of these changes, we investigated the ability of PN-FLX mice to extinguish learned fear ("fear extinction"), as performance in this behavioral paradigm is modulated by IL/PL output. Congruent with their altered IL/PL balance, PN-FLX mice display deficits in fear extinction learning and recall. Mimicking the diminished IL/PL ratio by selectively lesioning the IL, in control mice, phenocopied some features of the PN-FLX anxiety and depression-behavioral profile, demonstrating a causal relationship between mPFC changes and the emotional phenotype of PN-FLX mice. In the HC, PN-FLX treatment produced retraction of dendritic arbors but increased branching in the cornu ammonis 3 (CA3) sub-field. PN-FLX treatment also reduced total synapse number and synaptic density of CA3 neurons. In order to probe the functional consequences of these morphological changes, we investigated spatial learning in the Morris water maze and contextual fear conditioning in PN-FLX mice, as these behaviors are sensitive to CA3 manipulations. In line with reduced CA3 function, PN-FLX mice displayed deficits in both these learning paradigms. Taken together, our findings demonstrate that serotonin acts during a key developmental epoch to set the structural and physiological properties, and ultimately the functional output, of two key brain regions that underlie affective and cognitive behaviors, the mPFC and HC. Our findings provide a mechanism by which reported genetic (polymorphisms, mutations) and environmental factors (exposure to pharmacological agents or stress) that alter serotonergic tone during development, have long-term, often indelible, consequences on adult affective and cognitive function