Maturation of hippocampus-medial prefrontal cortex projections defines a pathway-specific sensitive period for cognitive flexibility

The septotemporal axis of the hippocampus separates it into domains with unique molecular, cellular, downstream connectivity, and behavioral profiles, and yet very little is known about the ontogenesis of these highly specialized subcircuits. Here, we use viral tracing, optogenetic-assisted patch clamping, chemogenetics, and behavior in mice to examine changes in domain-defined hippocampus efferent projections from postnatal day (P)10 to P60. We find distinct anatomical and synaptic developmental signatures in ventral and intermediate CA1 downstream connectivity, with unique contributions to the prelimbic and infralimbic subregions of the medial prefrontal cortex (mPFC). Juvenile inhibition of the ventral and intermediate CA1-mPFC pathways leads to opposing modulation of adult cognitive flexibility, establishing a sex- and pathway-specific sensitive period preceding the stabilization of CA1-mPFC synaptic transmission. Our data elucidate domain- and target-defined postnatal maturation of hippocampus efferents, indicating juvenility as a CA1-mPFC sensitive period with crucial implications for early life influences on adult cognition.