The role of the human memory-associated gene KIBRA in AMPA receptor trafficking and synaptic plasticity

Neuronal networks are constructed and undergo dynamic rearrangements instructed by experience. Activity-dependent changes in synaptic connectivity are widely believed to underlie learning and memory. A large body of work has shown that changes in the number or function of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors constitute a crucial mechanism by which synaptic plasticity occurs. AMPA receptors (AMPARs) are dynamically inserted and retrieved from synaptic sites under steady state conditions and in response to neuronal activity. Key to this receptor trafficking is a litany of AMPAR-interacting proteins that afford their tightly regulated synaptic targeting. One approach to understanding learning and memory has been to identify and functionally characterize the AMPAR-interacting proteins that control their trafficking. The synaptic PDZ and BAR domain-containing protein PICK1 is one such AMPAR-interacting protein that has been shown to play crucial roles in AMPAR trafficking and synaptic plasticity in several brain regions. Recent advances in genome-wide screening techniques have allowed genes associated with human memory to be revealed. These two complimentary methods for understanding higher brain function have converged with the identification of the human memory-associated gene KIBRA as a protein that directly binds PICK1. Despite compelling evidence that KIBRA is crucial for memory, the role of KIBRA at the molecular level in the brain is unclear.;In this study, we demonstrate that KIBRA exists in an AMPAR-trafficking complex in mouse brain along with the AMPAR subunits GluA1 and GluA2. The interaction between KIBRA and PICK1 is mediated by multiple protein interaction domains and is regulated by calcium. Using pH-GluA2 tagged receptors to monitor membrane trafficking of AMPARs, we find that KIBRA regulates activity-dependent AMPAR trafficking. In order to investigate a role for KIBRA in synaptic plasticity and learning and memory, we generated a KIBRA conditional knockout mouse. KIBRA is required for normal hippocampal synaptic plasticity in adult animals, but not in juveniles. Adult KIBRA knockout mice also have severe impairments in fear learning and memory. Finally, preliminary data suggests a role for an interaction partner of KIBRA, NF2, in AMPAR trafficking.