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.

Parvalbumin Interneuron Plasticity for Consolidation of Reinforced Learning.

Parvalbumin (PV) basket cells are widespread local interneurons that inhibit principal neurons and each other through perisomatic boutons. They enhance network function and regulate local ensemble activities, particularly in the γ range. Organized network activity is critically important for long-term memory consolidation during a late time window 11-15 h after acquisition. Here, we discuss the role of learning-related plasticity in PV neurons for long-term memory consolidation. The plasticity can lead to enhanced (high-PV) or reduced (low-PV) expression of PV/GAD67. High-PV plasticity is induced upon definite reinforced learning in early-born PV basket cells, whereas low-PV plasticity is induced upon provisional reinforced learning in late-born PV basket cells. The plasticity is first detectable 6 h after acquisition, at the end of a time window for memory specification through experience, and is critically important 11-15 h after acquisition for enhanced network activity and long-term memory consolidation. High- and low-PV plasticity appear to regulate activity in distinct local networks of principal neurons and PV basket cells. These findings suggest how flexibility and stability in learning and memory might be implemented through parallel circuits and networks.