AMPA RECEPTOR TYROSINE PHOSPHORYLATION AND SUBUNIT COMPOSITION

Throughout an organism’s lifespan, neural circuits mediate sensory and cognitive processing via synaptic plasticity, which involves synapse-specific Hebbian plasticity and network-level homeostatic plasticity. Synaptic strengthening and weakening are finely tuned by changes in postsynaptic AMPA-type glutamate receptors (AMPARs). Functional AMPAR tetramers are dimers of dimers, composed of combinations of four possible subunits, GluA1-4. Each AMPAR subunit has specific biophysical properties such as different ion permeability, conductance and desensitization, as well as unique regulation and trafficking properties. While previous studies have studied either the hippocampus or the whole brain, we evaluate AMPAR composition in the hippocampus and cortex, comparing both total and synaptic pools of AMPARs. We find that AMPAR composition between hippocampus and cortex are distinct, with GluA2/3 heteromers being the largest population in cortex and GluA1/2 being the major AMPARs in the hippocampus. We also discover a population of AMPARs, GluA1/3 heteromers, that are expressed in significant amounts in both cortical and hippocampal synapses, and do not originate from PV neurons. Furthermore, we have elucidated a novel biochemical regulation of AMPARs that is specific to homeostatic synaptic plasticity while sparing Hebbian plasticity mechanisms. Specifically, phosphorylation of the AMPAR subunit, GluA2, at tyrosine-876 is required for homeostatic synaptic strengthening by dictating the binding of GRIP1 – a crucial scaffolding protein – to GluA2. This finding provides an understanding of the mechanism through which a neuron can maintain a range of synaptic signaling whilst not compromising its responsiveness to subsequent salient synaptic activity