A Kv4.2-mGluR5 complex drives enhanced depotentiation in a mouse model of improved cognitive flexibility.

Memory updating promotes cognitive flexibility by enabling suppression of outdated information to optimize behavioral strategies in response to a changing environment. While some circuits involved have been identified, the synaptic mechanisms underlying this process remain uncertain. Here, using a recently developed Kv4.2 knock-in mouse model (Kv4.2TA), we identify a metaplasticity in the hippocampus that accompanies an improvement in cognitive flexibility. Mutation of a C-terminal phosphorylation site (T607) in the alpha subunit of the voltage-gated K+ channel protein Kv4.2 drives boosted depotentiation of spike timing-dependent long-term synaptic potentiation mediated by mGluR5 receptors, putative constituents of Kv4.2 macromolecular complexes. We found that mGluR5 receptors are required for the improved cognitive flexibility observed in Kv4.2TA mice. These findings reveal a synaptic correlate associated with memory updating in cognitive flexibility and spotlight the Kv4.2-mGluR5 complex as a therapeutic target for disorders characterized by impairments in cognitive flexibility.