Abstract
Despite the physiological significance and linkage to schizophrenia, little is known about the posttranslational regulation of a major glial glutamate transporter GLAST. GLAST abounds at perisynaptic membrane domains in Bergmann glia and interacts with submembranous cytoskeletal components including septins（polymerizing GTPases）, myosin-10, and CDC42EP4（CDC42 effector protein 4）whose roles had been unknown. In Cdc42ep4-/- mice, GLAST is dissociated from septins, and delocalized away from synaptic active zones. Electrophysiological analysis of the prarallel fiber-Purkinje cell synapses revealed protracted decay time constant in the excitatory postsynaptic current, and excessive baseline inward current in response to a subthreshold dose of a nonselective inhibitor of the glutamate transporters. The insufficient glutamate-buffering/clearance capacity in these mice manifested as motor coordination/learning defects, which were aggravated with the inhibitor at a subthreshold dose. These findings indicate that the CDC42EP4/septin-based glial scaffold facilitates perisynaptic localization of GLAST and optimizes the efficiency of glutamate-buffering and clearance. Given the accumulation and/or upregulation of several septin subunits and CDC42EP4 in dorsolateral prefrontal cortex in postmortem brains with schizophrenia and bipolar disorders, the resulting glutamate dysregulation may modulate pathophysiology of the psychiatric disorders.
