Abstract
The cerebellum is sensitive to ethanol (EtOH) consumption. Chronic EtOH consumption impairs motor learning by modulating the cerebellar circuitry synaptic transmission and long-term plasticity. Under in vitro conditions, acute EtOH inhibits both parallel fiber (PF) and climbing fiber (CF) long-term depression (LTD). However, thus far it has not been investigated how chronic EtOH consumption affects sensory stimulation-evoked LTD at the molecular layer interneurons (MLIs) to the Purkinje cell (PC) synapses (MLI-PC LTD) in the cerebellar cortex of living animals. In this study, we investigated the effect of chronic EtOH consumption on facial stimulation-evoked MLI-PC LTD, using an electrophysiological technique as well as pharmacological methods, in urethane-anesthetized mice. Our results showed that facial stimulation induced MLI–PC LTD in the control mice, but it could not be induced in mice with chronic EtOH consumption (0.8 g/kg; 28 days). Blocking the cannabinoid type 1 (CB1) receptor activity with AM-251, prevented MLI-PC LTD in the control mice, but revealed a nitric oxide (NO)-dependent long-term potentiation (LTP) of MLI–PC synaptic transmission (MLI-PC LTP) in the EtOH consumption mice. Notably, with the application of a NO donor, S-nitroso-N-Acetyl-D, L-penicillamine (SNAP) alone prevented the induction of MLI–PC LTD, but a mixture of SNAP and AM-251 revealed an MLI-PC LTP in control mice. In contrast, inhibiting NO synthase (NOS) revealed the facial stimulation-induced MLI-PC LTD in EtOH consumption mice. These results indicate that long-term EtOH consumption can impair the sensory stimulation-induced MLI–PC LTD via the activation of a NO signaling pathway in the cerebellar cortex in vivo in mice. Our results suggest that the chronic EtOH exposure causes a deficit in the cerebellar motor learning function and may be involved in the impaired MLI–PC GABAergic synaptic plasticity.
Highlights
The cerebellum is an important organ controlling motor coordination, planning and fine regulating voluntary movement, and is critical for cognitive functions, such as thought, behavior and emotion
We found that facial stimulation induced long-term depression (LTD) at molecular layer interneurons (MLIs)-Purkinje cell (PC) synapses (MLIPC LTD), accompanied with a decrease in the stimulationevoked pause of spike firing in PCs via activation of NMDA receptors in the mouse cerebellar cortex, suggesting that sensory stimulation evoked MLI-PC GABAergic synaptic plasticity may play a critical role in motor learning of living animals (Bing et al, 2015)
The normalized value of the SS pause, at 40–50 min after 1 Hz facial stimulation, was decreased to 71.2 ± 7.6% of the baseline (100.0 ± 7.1%; P < 0.05, n = 7, Figure 2D). These results indicate that 1 Hz facial stimulation induces MLI-PC LTD in the cerebellar cortex of control mice
Summary
The cerebellum is an important organ controlling motor coordination, planning and fine regulating voluntary movement, and is critical for cognitive functions, such as thought, behavior and emotion. EtOH consumption causes alterations of motor coordination, balance, behavior, speech, and certain cognitive functions. It has been assumed that some of the behavioral actions of EtOH are mediated by enhancing the inhibitory action of GABA (Martz et al, 1983; Criswell and Breese, 2005; Weiner and Valenzuela, 2006; Botta et al, 2010). EtOH increases the frequency of miniature and spontaneous inhibitory postsynaptic currents at PCs and MLIs in rat cerebellar slices, via increasing the GABA release (Mameli et al, 2008; Hirono et al, 2009; Wadleigh and Valenzuela, 2012), and modulating facial stimulation-evoked GABAergic responses in the mouse cerebellar cortical molecular layer (Cui et al, 2014)
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