KIBRA Regulates AMPA Receptor Expression, Synaptic Plasticity, and Memory in an Age-Dependent Manner

Abstract

The biological mechanisms supporting age-dependent changes in learning and memory remain elusive. While a growing body of human literature implicates KIBRA in memory and neurodevelopmental disorders, KIBRA’s molecular function and contribution to maturation of synaptic function and cognition remain poorly understood. Despite being expressed throughout early postnatal development, germline deletion of KIBRA impairs synaptic plasticity selectively in adult rodents. However, it is unclear whether KIBRA facilitates proper brain maturation necessary for adult plasticity or whether it plays a distinct role in plasticity in the adult brain. Here, using an inducible KIBRA knockout mouse, we demonstrate that acutely deleting KIBRA in adult forebrain neurons impairs both spatial memory and long-term potentiation (LTP). The deficits in LTP correlate with an adult-selective decrease in extrasynaptic AMPA receptors under basal conditions. We also identify a novel role for KIBRA in LTP-induced AMPAR upregulation. In contrast, acute deletion of KIBRA in juvenile forebrain neurons did not affect LTP and had minimal effects on basal AMPAR expression. 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.Significance StatementSynaptic plasticity supported by trafficking of postsynaptic AMPA receptors is a conserved mechanism underlying learning and memory. The nature and efficacy of learning and memory undergo substantial changes during childhood and adolescent development, but the mechanisms underlying this cognitive maturation remain poorly understood. Here, we demonstrate that the human memory- and neurodevelopmental disorder-associated gene KIBRA facilitates memory and hippocampal synaptic plasticity selectively in the adult hippocampus. Furthermore, we show that selective loss of KIBRA from adult but not juvenile neurons reduces expression of extrasynaptic AMPA receptors and prevents LTP-induced increases in AMPAR expression. Overall, our results suggest that KIBRA participates in cellular and molecular processes that become uniquely necessary for memory and synaptic plasticity in early adulthood.

Experience alters hippocampal and cortical network communication via a KIBRA-dependent mechanism

“…During pre-experience home cage periods, there was no significant difference in SWR-based gamma power between genotypes (Fig. 3F), in agreement with a lack of basal changes in synaptic function and SWR properties in KIBRA cKO mice( 8, 10 ) (Fig. 1J-O).…”

“…The occurrence rate of SWRs has been shown to transiently increase following salient experience( 50-52 ), an effect that is blocked by systemic pharmacological inhibition of NMDA receptors( 53 ). Given KIBRA’s critical role in synaptic plasticity( 8-10 ), we hypothesized that changes in SWR drive following experience would be reduced in KIBRA cKO mice. However, both WT and KIBRA cKO mice displayed similar experience-dependent modulation of SWR rate (Fig.…”

“…KIBRA plays a key role in regulating AMPAR trafficking, synaptic plasticity, learning and memory (8)(9)(10)(11). Substantiating this crucial role are numerous human genetic studies that implicate KIBRA in memory and disorders of complex cognition (12,13,16,18,21,67).…”

“…The synapse-enriched protein KIBRA (Kidney and Brain protein, a.k.a. WWC1) is a post-synaptic scaffold that regulates AMPAR trafficking (8)(9)(10).…”

“…The synapse-enriched protein KIBRA ( Ki dney and Bra in protein, a.k.a. WWC1) is a post-synaptic scaffold that regulates AMPAR trafficking( 8-10 ). Accordingly, KIBRA is acutely required in the adult brain for learning and memory as well as synaptic plasticity( 8-11 ).…”