Chronic ethanol exposure during adolescence impairs simple spike activity of cerebellar Purkinje cells in vivo in mice

Cerebellar Purkinje cells (PCs) play critical roles in motor coordination and motor learning through their simple spike (SS) activity. Previous studies have shown that chronic ethanol exposure (CEE) in adolescents impairs learning, attention, and behavior, at least in part by impairing the activity of cerebellar PCs. In this study, we investigated the effect of CEE on the SS activity in urethane-anesthetized adolescent mice by in vivo electro-physiological recordings and pharmacological methods. Our results showed that the cerebellar PCs in CEE adolescent mice expressed a significant decrease in the frequency and an increase in the coefficient of variation (CV) of SS than control group. Blockade of gamma-aminobutyric acid A (GABA(A)) receptor did not change the frequency and CV of SS firing in control group but produced a significant increase in the frequency and a decrease in the CV of SS firing in CEE mice. The CEE-induced decrease in SS firing rate and increase in CV were abolished by application of an N-methyl-D-aspartate (NMDA) receptor blocker, D-APV, but not by an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, NBQX. Notably, the spontaneous spike rate of molecular layer interneurons (MLIs) in CEE mice was significantly higher than control group, which was also abolished by application of D-APV. These results indicate that adolescent CEE enhances the spontaneous spike firing rate of MLIs through activation of NMDA receptor, resulting in a depression in the SS activity of cerebellar PCs in vivo in mice.