Mendoza, M. L. | Search bioRxiv

bioRxiv2022

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

Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate systems-level memory consolidation coordinated by SWRs and cortical sleep spindles. However, it remains unclear how molecular changes at synapses contribute to experience-induced modification of network function. The synaptic protein KIBRA regulates plasticity and memory, although its impact on circuit dynamics remains unknown. Here, we recorded in vivo neural activity from WT mice and littermates lacking KIBRA to examine circuit function before, during, and after novel experience. In WT mice, experience altered network dynamics in a manner consistent with incorporation of new information content in replay and enhanced hippocampal-cortical communication. However, while baseline SWR features were normal in KIBRA cKO mice, experience-dependent alterations in SWRs were absent. Furthermore, intra-hippocampal and hippocampal-cortical communication during SWRs was disrupted following KIBRA deletion. These results reveal molecular mechanisms that underlie network-level memory formation and consolidation.

neuroscience↗

bioRxiv2022

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

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, KIBRAs 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.

neuroscience↗