Ethanol disrupts cerebellar synaptic modulation by enhancing EAAT4-mediated glutamate uptake.

Ataxia is a common consequence of alcohol consumption. Although ethanol enhances GABAergic neurotransmission in the cerebellum, its effects on glutamatergic synaptic signaling remain unclear. Electrophysiological studies in rat cerebellar slices have shown that ethanol, at pharmacologically relevant concentrations (25-100 mM), restricts the diffusion of excitatory neurotransmitters from synaptic clefts into the extracellular space. This restriction suppresses intersynaptic modulation between glutamatergic climbing fibers and GABAergic molecular layer interneurons that converge on the same Purkinje cell. This effect is mediated by increased glutamate uptake via the excitatory amino acid transporter EAAT4 in Purkinje cells, operating in concert with the sodium pump (Na,K-ATPase, NKA). Enhanced EAAT4 activity may represent a central mechanism underlying alcohol-induced cerebellar dysfunction. These findings indicate that neuronal EAATs function both as clearance systems and dynamic modulators of synaptic signaling. Ethanol-induced upregulation of glutamate uptake may inform therapeutic strategies targeting EAAT and NKA to prevent excitotoxic neuropathies.