Pro-cognitive restoration of PV interneuron plasticity in neurodevelopmental disorders

To identify candidate regulators of experience-dependent PV IN plasticity genes or “XPGs” in CA3/CA2 PV INs, we designed an in vivo functional screen in adult mice to isolate translated mRNAs from CA3/CA2 PV INs that receive increased mossy fiber inputs, a trigger for experience-dependent PV IN plasticity. We virally downregulated a molecular brake of mossy fiber filopodia-PV IN connectivity, Ablim3 (Non-target shRNA (shNT) vs. shAblim3-RNA), in DG mossy fibers, to reproduce the effects of experience on mossy fiber filopodial inputs onto PV INs. We used PV-Cre; Rpl22HA/HA mice, in which expression of the hemagglutinin (HA) epitope-tagged ribosomal protein L22 (Rpl22) is restricted to PV INs. Following optimization of signal-to-noise for mRNA isolation from this extremely sparse population of PV INs , we compared mRNAs biochemically isolated from genetically tagged PV INs in the naïve state versus an experience-induced activated state in CA3/CA2. Using this approach we identified differentially expressed candidate XPGs associated with the PV IN activated state.