Ubiquitination of the GluA1 subunit of AMPA receptors is required for synaptic plasticity, memory and cognitive flexibility.

Activity-dependent changes in the number of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs) at the synapse underpin the expression of long-term potentiation (LTP) and long-term depression (LTD), cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator 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 synapses. 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 synaptic plasticity, learning and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit 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. Significance statement: Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPA receptors for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPA receptors required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-beta (Aβ) cause excessive ubiquitination of GluA1, inhibiting GluA1 ubiquitination may have the potential to ameliorate Aβ-induced synaptic depression in Alzheimer's disease.