Physiological role of neuronal glutamate transporters: control of extrasynaptic glutamate diffusion-mediated modification of synaptic transmission

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In response to repetitive activation of the climbing fibers (CFs), GABA release at basket cell (BC)-Purkinje cell (PC) synapses in the cerebellar cortex is suppressed through extrasynaptic diffusion of the CF transmitter glutamate and following activation of AMPA receptors that expressed on BC axon terminals. We found that the CF-induced presynaptic inhibition of cerebellar GABAergic transmission is suppressed by ethanol (EtOH) at a clinically relevant concentration (25-50 mM). Pharmacological blockade of the neuronal glutamate transporter EAAT4 not only augmented the CF-induced inhibition of GABAergic transmission but also abolished the suppressive action of EtOH on the CF-induced inhibition. This EtOH action was diminished by inhibitors for protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K). These results suggest that EtOH acutely potentiates EAAT4-mediated glutamate uptake in PCs through PKC/PI3K-mediated protein phosphorylation.