THE INTRACELLULAR MOLECULAR MECHANISMS UNDERLYING GLUA3-CONTAINING AMPA-RECEPTOR PLASTICITY

In pyramidal neurons of the mature hippocampus, the majority of AMPA receptors (AMPARs) consist of subunits GluA1 and GluA2, or GluA2 and GluA3. Depending on the composition of these AMPARs, the contribution to synaptic plasticity and, consequently, to memory processing differs. Unlike GluA1-containing AMPARs, GluA3-containing AMPARs traffic into synapses independent of activity and because they are electrically silent under basal conditions, GluA3 contributes little to synaptic transmission. Under heightened emotional states, neuromodulators, such as noradrenaline, can increase intracellular cyclic AMP (cAMP) levels, causing GluA3-containing AMPARs to switch to an electrically conductive state. However, the exact signaling cascade by which GluA3-containing AMPARs become electrically conductive remains unclear. This project aims to identify the specific intracellular molecular mechanism involved in cAMP-mediated GluA3-dependent plasticity. We observed that PKA, the canonical cAMP-dependent pathway, is not involved in mediating GluA3-plasticity in hippocampal neurons. Epac, the other cAMP target protein, did not contribute to GluA3-dependent plasticity. Instead, our data suggest that cAMP activates GluA3 through Ras activation. Pharmacological intervention while recording excitatory postsynaptic currents in CA1 neurons in organotypic hippocampal cultures of WT and GluA3 knockout mice, showed that GluA3-dependent plasticity remained intact in the presence of a MEK inhibitor but was abolished by PI3K inhibition. This suggests that PI3K, as a downstream target of Ras, is most likely involved in GluA3-dependent plasticity. Together, these findings contribute to a better understanding of how GluA3-containing AMPARs might contribute to learning and memory processing.