Alcohol abuse, in combination with multiple alcohol withdrawal events, produces a phenomenon similar to kindling in subcortical structures. Depending on the duration of alcohol consumption and the number of withdrawal events the clinical symptoms of alcohol withdrawal can range from mild to gross tremors, hyperactivity, confusion, hallucinations, sleep disruption and seizures. These symptoms can worsen with each withdrawal event and complicate diagnosis and treatment. Underlying withdrawal seizure is an abnormal brain rhythm that is produced in the thalamus by neurons firing rhythmic bursts of action potentials. These bursts depend upon a class of T-type calcium channels that are expressed within the brain and periphery. Despite the similarities between alcohol withdrawal seizures and other generalized seizures of thalamic origin, the influence of ethanol on thalamic function during alcohol withdrawal is unknown. This is particularly important to understand because abnormal thalamic rhythms precede the generalization of abnormal rhythms in both the hippocampus and the cerebral cortex. The overall goal of this proposal is to determine cellular and molecular mechanisms underlying alterations in thalamic T-type calcium channels in response to multiple withdrawal events and how these contribute to alcohol withdrawal seizure. A mouse model will be used to explore these mechanisms because it possesses all three of the T-type calcium channel isoforms, and is a well-developed model for multiple withdrawal seizures. In addition, it will allow us to integrate a knockout of a highly ethanol-sensitive T-type channel isoform in our studies.
In Aim 1, we propose to record withdrawal seizures and, using spike train analyses we have developed, to characterize the specific contribution of T-type channel burst discharges to the development of seizure.
In Aim 2, we will characterize the molecular mechanisms underlying the development of burst firing in subcortical structures, and we will relate the incidence of bursts to the gene and protein increases we have observed in our preliminary studies.
In Aim 3, we will use high resolution whole cell patch recordings to determine whether the increases in gene and protein expression we have observed produce simple increases in calcium currents, or more complex alterations in basic channel kinetics.
We will examine the influence of ethanol on an ethanol-sensitive calcium channel that underlies alcohol withdrawal seizure. In addition to the brain, this channel is involved in the basic biology and dysfunction of the heart, lung and liver, and is expressed in certain cancers, thus studies of the molecular regulation of this channel are highly significant to human health generally, and are specifically relevant to the understanding of alcohol withdrawal. ? ? ?
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