Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a <i>Mecp2</i> mouse model for Rett syndrome

Social memory impairments in <i>Mecp2</i> 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 (RTT), 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 (PYRs) and mPFC PYRs and parvalbumin interneurons (PV-INs) resulting in social memory impairments in <i>Mecp2</i> KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in <i>Mecp2</i> KO mice using a new four-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca²⁺-sensor signals during social interactions. mPFC PYRs of wild-type (WT) mice showed increases in the amplitude of population Ca²⁺ signals during explorations of a novel toy mouse and interactions with both familiar and novel mice, whereas PYRs of <i>Mecp2</i> KO mice showed smaller population Ca²⁺ signals during interactions only with live mice. On the other hand, mPFC PV-INs of <i>Mecp2</i> KO mice showed larger population Ca²⁺ signals during interactions with a familiar cage-mate compared with 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 <i>Mecp2</i> KO mice during social interactions, potentially driving their deficit in social memory.<b>NEW & NOTEWORTHY</b> The hippocampus is hyperactive in a mouse model for Rett syndrome, and such atypically heightened activity propagates to the medial prefrontal cortex (mPFC) through a monosynaptic projection, resulting in altered mPFC activity and social memory deficits. Here, we used fiber photometry of population Ca²⁺ signals as surrogates of neuronal activity, and show that atypically heightened inhibition from pyramidal neuron (PYR)-targeting GABAergic parvalbumin interneurons, and impaired PYR activity in the mPFC of Rett mice during social interactions, driving their deficit in social memory.