Hippocampal input-driven plasticity of prefrontal interneurons reveals a circuit basis for impaired spatial working memory.

Dynamic functional connectivity between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) is essential for spatial working memory (SWM). Interactions between vHPC projections and mPFC interneurons, and their plasticity, are uniquely positioned to influence SWM, yet the nature of these interactions remains unclear. Here, we combined in vivo optical stimulation of vHPC inputs to mPFC with calcium recordings of discrete mPFC interneuron populations in mice, revealing class-specific response profiles and plasticity. Repeated vHPC input stimulation persistently depressed activity in vasoactive intestinal peptide (VIP)-expressing interneurons and potentiated activity in somatostatin-expressing interneurons. Ex vivo whole-cell electrophysiology and computational modeling revealed that these divergent effects likely arise from a primary weakening of monosynaptic vHPC input onto VIP interneurons. Leveraging this plasticity to inform the circuit interactions that support SWM, we found that mice with prior vHPC input stimulation displayed elevated VIP interneuron activity during the delay epoch in early SWM task training, and this enhanced activity correlated with poorer training performance. Accordingly, mice modeling the schizophrenia-predisposing 22q11.2 deletion syndrome with known SWM learning deficits recapitulated this aberrant VIP interneuron activity profile and showed reduced vHPC targeting of mPFC VIP interneurons. Together, these findings reveal novel cell-type-specific plasticity in cognition-supporting circuits and illustrate how reweighting of inputs to VIP interneurons may contribute to working memory dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/665987v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@29a326org.highwire.dtl.DTLVardef@1964208org.highwire.dtl.DTLVardef@1c94e4corg.highwire.dtl.DTLVardef@1336edb_HPS_FORMAT_FIGEXP M_FIG C_FIG IN BRIEFSilverstein et al. investigated how ventral hippocampus (vHPC) inputs to medial prefrontal cortex (mPFC) interact with mPFC interneuron populations to support spatial working memory (SWM) in mice. They show that repeated vHPC input stimulation that reduces vHPC drive onto vasoactive intestinal peptide (VIP) interneurons also elevates delay-related VIP interneuron activity in early SWM task training, and this enhanced activity correlates with poorer training performance. Mice modelling the 22q11.2 deletion syndrome--known to have SWM learning deficits--recapitulate this altered VIP interneuron activity and show reduced vHPC input targeting of VIP interneurons. HIGHLIGHTSO_LIRepeated stimulation of vHPC inputs to mPFC persistently depresses VIP interneuron activity and enhances SST interneuron activity in mice C_LIO_LIBlunted monosynaptic drive onto mPFC VIP interneurons by repeated vHPC input stimulation plausibly reproduces in vivo activity changes C_LIO_LIStimulated mice show heightened VIP interneuron activity during the delay epoch in early SWM task training that correlates with poorer training performance C_LIO_LIMice modeling the 22q11.2 deletion syndrome with known SWM task learning deficits mirror this aberrant VIP interneuron activity profile and show reduced vHPC input targeting of VIP interneurons C_LI