Selective vulnerability of the ventral hippocampus-prelimbic cortex axis parvalbumin interneuron network underlies learning deficits of fragile X mice.

High-penetrance mutations affecting mental health can involve genes ubiquitously expressed in the brain. Whether the specific patterns of dysfunctions result from ubiquitous circuit deficits or might reflect selective vulnerabilities of targetable subnetworks has remained unclear. Here, we determine how loss of ubiquitously expressed fragile X mental retardation protein (FMRP), the cause of fragile X syndrome, affects brain networks in Fmr1y/- mice. We find that in wild-type mice, area-specific knockout of FMRP in the adult mimics behavioral consequences of area-specific silencing. By contrast, the functional axis linking the ventral hippocampus (vH) to the prelimbic cortex (PreL) is selectively affected in constitutive Fmr1y/- mice. A chronic alteration in late-born parvalbumin interneuron networks across the vH-PreL axis rescued by VIP signaling specifically accounts for deficits in vH-PreL theta-band network coherence, ensemble assembly, and learning functions of Fmr1y/- mice. Therefore, vH-PreL axis function exhibits a selective vulnerability to loss of FMRP in the vH or PreL, leading to learning and memory dysfunctions in fragile X mice.