Perirhinal cortex abnormalities impair hippocampal plasticity and learning in <i>Scn2a</i> , <i>Fmr1</i> , and <i>Cdkl5</i> autism mouse models

Learning and memory deficits, including spatial navigation difficulties, are common in autism spectrum disorder (ASD). Several ASD mouse models (<i>Scn2a^+/-</i>, <i>Fmr1^-/-</i>, <i>Cdkl5^-/-</i>) exhibit impaired spatial learning, with these deficits often attributed to hippocampal dysfunction. However, we identify the perirhinal cortex (PRC) as a critical driver of these deficits. Cortical-wide <i>Scn2a</i> reduction in excitatory neurons replicated the spatial learning and long-term potentiation (LTP) impairments-a cellular correlate of learning-seen in <i>Scn2a^+/-</i> mice, while hippocampal-wide reduction did not. PRC-specific viral-mediated <i>Scn2a</i> reduction in excitatory neurons decreased release probability, which consequently disrupted synaptic transmission and LTP in the hippocampus, as well as spatial learning. As PRC activity was reduced, chemogenetic activation of the PRC reversed these deficits in <i>Scn2a^+/-</i> mice and rescued spatial learning and LTP impairments in <i>Fmr1</i> and <i>Cdkl5</i> knockout mice. Thus, in several genetic models of ASD, PRC abnormalities may disrupt hippocampal function to impair learning and memory.