Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Abstract

Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca 2ϩ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber3 Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mM (legal blood alcohol level in the United States is below 0.08 g/dl ϭ 17 mM).

Ethanol Inhibits Persistent Activity in Prefrontal Cortical Neurons

“…However, results from studies from our laboratory show that, in acute slices, synaptic NMDA currents from deep-layer PFC neurons are reliably inhibited by moderate (44 mM) concentrations of ethanol whereas those generated by AMPA or GABA A receptors are mostly unaffected (our unpublished observations). These findings are generally consistent with other studies showing that ethanol has little effect on most AMPA-mediated EPSCs (Lovinger et al, 1989;Weiner et al, 1999) (but see Mameli et al, 2005;Carta et al, 2006) and has variable effects on GABA-mediated currents (for review, see Weiner and Valenzuela, 2006). Importantly, NMDA-dependent response processes are consistently reported to be inhibited by ethanol including those from hippocampus (Lovinger et al, 1990), posterior cingulate (Li et al, 2002), nucleus accumbens (Nie et al, 1994), and amygdala (Roberto et al, 2004).…”

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

“…Many biological phenomena contribute to ethanolinduced responses. These include the involvement of neuropeptide-Y related pathways, [1][2][3][4] glutamate receptors, 5,6 GABA receptors, 7,8 the cAMP signalling pathway, 9,10 the BK potassium channel, SLO-1 [11][12][13] , and membrane perturbation. 14 Many genes and proteins are conserved between Caenorhabditis elegans and humans, including many of those that have been identified as playing a possible role in the effects of ethanol.…”

Comparative assessments of the effects of alcohol exposure on fetal brain development using optical coherence tomography and ultrasound imaging

“…1 Previous research has shown that ethanol can directly affect various aspects of brain development in the fetus. [2][3][4] Similarities in development between humans and mice have led to wide usage of fetal mice as models for human developmental diseases. Alcohol-exposed pregnant mice have previously been used to study the emergence of FASD during fetal development.…”