The effects of alcohol on cerebellar synaotic transmission and plasticity

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DESCRIPTION (provided by applicant): Plasticity in brain motor systems allows fine adjustments of motor coordination that can develop over long periods of time, but can also occur within minutes. Rapid motor learning rests on synaptic plasticity at excitatory synaptic inputs to cerebellar Purkinje cells. Synaptic gain changes such as long-term potentiation (LTP) and long-term depression (LTD) at parallel fiber (PF) and climbing fiber (CF) synapses onto Purkinje cells provide a cellular basis for cerebellar motor learning. Alcohol is known to interfere with synaptic transmission and plasticity, but acute alcohol effects on cerebellar synaptic plasticity have not been studied so far, although it is well known that acute consequences of alcohol consumption include the impairment of motor coordination and the ability to fine-tune movements. Here, we propose to examine the effects of acute ethanol application on cerebellar synaptic plasticity in rat brain slices using whole-cell patch-clamp recordings as well as microfluorometric imaging techniques. Aside from our preliminary experiments performed in preparation for this application, we have no previous experience in alcohol-related research. However, we have characterized cellular mechanisms underlying cerebellar synaptic plasticity (e.g. Hansel et al., 2001; Jvrntell and Hansel, 2006). This application for financial support from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is motivated by our hope that we now have the required experience and tools at hand to study how ethanol interferes with cerebellar learning mechanisms. Our first steps into the field of alcohol research will be facilitated by a collaboration with the laboratory of Prof. C.F. Valenzuela (University of New Mexico at Albuquerque, USA), who has long-standing experience in this field. Here, we suggest three specific aims: a) to examine acute ethanol effects on cerebellar synaptic transmission and synaptic plasticity, b) to examine ethanol effects on NMDA receptors, metabotropic glutamate receptors and voltage-dependent calcium channels in Purkinje cells and c) to use calcium imaging techniques, in combination with somato-dendritic patch-clamp techniques, to monitor ethanol effects on the spatio-temporal map of dendritic calcium spikes in Purkinje cell dendrites. These dendritic calcium spikes, which are crucial for cerebellar plasticity, are likely triggered by voltage-gated calcium currents and NMDA receptors. Both have been described as ethanol targets in other types of neurons, and therefore dendritic calcium spikes might be affected by ethanol as well. Our proposal has an innovative and exploratory character, as we plan to use a novel combination of imaging (ultra high-speed calcium imaging) and patch-clamp techniques (triple patching with one somatic and two dendritic locations) to be able to characterize dendritic calcium spike activity, which has not been done so far in alcohol research. We believe that this type of research is important to better understand the cellular basis of acute effects of alcohol consumption. One of these is impaired motor coordination, which contributes to the high rate of deaths caused by alcohol-related traffic accidents. PUBLIC HEALTH RELEVANCE: The cerebellum is a brain structure involved in the fine-adjustment of motor coordination and in motor learning. These processes can be impaired as a consequence of acute alcohol consumption, and yet acute alcohol effects on cerebellar synaptic transmission and on plasticity within cerebellar networks have not been studied so far. Here, we propose to examine alcohol effects on forms of cerebellar synaptic plasticity as well as the cellular causes for such effects using electrophysiological recording techniques and fluorometric calcium imaging techniques in rat brain slices.