KIBRA regulates activity-induced AMPA receptor expression and synaptic plasticity in an age-dependent manner

Summary: A growing body of human literature implicates KIBRA in memory and neurodevelopmental disorders. Memory and the cellular substrates supporting adaptive cognition change across development. Using an inducible KIBRA knockout mouse, we demonstrate that adult-onset deletion of KIBRA in forebrain neurons impairs long-term spatial memory and long-term potentiation (LTP). These LTP deficits correlate with adult-selective decreases in extrasynaptic AMPA receptors under basal conditions, and we identify a role for KIBRA in LTP-induced AMPAR upregulation. In contrast, juvenile-onset deletion of KIBRA in forebrain neurons did not affect LTP and had minimal effects on basal AMPAR expression. LTP did not increase AMPAR protein expression in juvenile WT mice, providing a potential explanation for juvenile resilience to KIBRA deletion. These data suggest that KIBRA serves a unique role in adult hippocampal function through regulation of basal and activity-dependent AMPAR proteostasis that supports synaptic plasticity.