Frmpd2 Regulates 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 Frmpd2 is specifically expressed in postsynaptic membrane within neurons of adult hippocampus and cortex.Frmpd2 effectively alters the neuronal excitability by regulating NMDARs-component excitatory synaptic transmission.Frmpd2 anchors the NMDAR subunit NR2 A,not NR2 B or NR1 at the plasma membrane without changing the total NMDAR expression.By using of Co-IP,Pull Down and SPR,the second PDZ(PDZ2)domain of Frmpd2 direct and strong binds to the C-terminus of NR2 A.It is further supported by an undescribed crystal structure of mouse Frmpd2 PDZ2.Moreover,Ferm domain of Frmpd2 directly interacts with actin filaments,providing the strongest support for surface NR2 A anchoring.Frmpd2 also affects excitatory synapse morphogenesis,further strengthen neuronal excitatory transmission.In particular,Frmpd2 mediates the behavioral and field potential phenotypes of epilepsy,a brain disorder of excitability.Our study discover that a novel scaffold protein Frmpd2 regulates synaptic excitatory in a PDZ2 domain-and Ferm domain-interdependent manner in adult hippocampus.