Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expres-sion of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key reg-ulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synap-ses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synap-tic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but ex-hibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.