The excitatory amino acid pathways in the brain are widespread and are involved in synaptic plastic events such as long-term potentiation in the hippocampus. Long-term potentiation is thought to be part of the process of learning and memory. Excitatory amino acids are thought to also play a role in excitotoxicity as related to seizures and may be involved in ethanol withdrawal induced seizures. At least two glutamatergic receptor systems are thought to regulate long-term potentiation in the hippocampus. These receptor systems are the metabotropic receptors and the NMDA receptor complex. The metabotropic receptors are G-protein linked receptors that are coupled to several intracellular enzymes such as phospholipase C. The NMDA receptor is a complex of several protein subunits that form a glutamate gated ion channel that has high permeability for calcium. Each subunit imparts a different character to the NMDA receptor function. Acute and chronic treatment with ethanol alters the function of these receptors. Prenatal exposure to ethanol can affect the offspring even when they are quite old. Alteration of these receptors in the hippocampus by ethanol can influence the process of learning and memory. We now know that chronic ethanol treatment increases the function of NMDA receptor in the hippocampus and that an increase in the protein for NR1 NMDA subunit is observed as well as an increase in binding sites for NMDA. Prenatal exposure to ethanol causes a decrease in both NMDA receptor function and metabotropic receptor function.
The specific aims of these investigations are to examine what metabotropic receptor subtypes and/or what NMDA receptor subunits change after chronic ethanol exposure or prenatal ethanol exposure and how these changes in protein expression correllate with functional chages. We will be using receptor subtype and subunit specific antibodies to identify and quantify metabotropic receptor subtypes and NMDA receptor NR1 splice variants and NR2 subunits that may change after such an insult. My long-term goal is to understand how differences in the expression of metabotropic receptors and NMDA receptor subunits occur during chronic and prenatal ethanol treatments. These studies will help us to understand some of the underlying mechanism in fetal alcohol syndrome as well as the effects of chronic alcoholism.
