FRMPD2: a novel GluN2A-interacting scaffold protein in synaptic excitatory transmission

The scaffold proteins FRMPD2 is localized at the basolateral membranes of polarized epithelial cells and associated with tight junction formation. But the expression and function of FRMPD2 in vivo remain unknown. Here, we found that postsynaptic FRMPD2 effectively alters the neuronal excitability by regulating NMDARs-component excitatory synaptic transmission in adult hippocampus. FRMPD2 anchors the NMDAR subunit GluN2A at the synapses without changing the total NMDAR expression. By using of Co-IP, Pull Down and SPR, the second PDZ (PDZ2) domain of FRMPD2 direct and binds to the C-terminus of GluN2A. Moreover, Ferm domain of FRMPD2 directly interacts with actin filaments and modifies excitatory synapse morphogenesis, further strengthen neuronal excitatory transmission. In particular, FRMPD2 mediates the behavioral and field potential phenotypes of epilepsy, a brain disorder of excitatory/inhibitory imbalance. Our study discover that a novel scaffold protein FRMPD2 regulates synaptic excitatory in a PDZ2 domain- and Ferm domain-dependent manner in adult hippocampus.