Abstract
Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca(2+)-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca(2+) signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca(2+) signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca(2+) signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.