Prenatal ethanol exposure in the developing human CNS can result in severe mental retardation linked to fetal alcohol syndrome or associated attention disorders and hyperactivity. There is an enhanced sensitivity to the teratogenic effects of ethanol during the third trimester which correlates with the onset of the brain growth spurt period in humans. Animal studies have confirmed that ethanol exposure during the brain growth spurt induces severe neuronal loss. The cerebellar region of the developing rat CNS is highly sensitive to ethanol, with decreases in the number of granule and Purkinje cells and cerebellar size, changes in neuronal excitability, and delayed neuronal differentiation and synapse formation all consequences of ethanol treatment. Although the mechanisms underlying ethanol action in the developing CNS remain to be established, several transmembrane signaling systems in neuronal membranes are known to be affected by ethanol exposure. Recent evidence has indicated that excitatory amino acid (EAA) receptors, particularly the NMDA receptor, may be especially sensitive neurochemical targets for the pharmacological properties of ethanol in brain. In addition, many EAA receptor second messenger responses display a transient developmental expression that peaks during the brain spurt, and coincides with a period of heightened sensitivity to the teratogenic effects of ethanol. This has generated great interest in the potential of EAA receptors as potential targets for some of the neurotoxic properties of ethanol in the developing CNS. In this project we will examine the mechanism(s) by which ethanol interferes with excitatory amino acid (EAA) neurotransmission. An increase in cytosolic free calcium ([Ca2+]/i) is central to many of the physiological and pathophysiological properties of EAAs in the developing central nervous system (CNS), and can be initiated by activation of both ionotropic and metabotropic EAA receptors. Ionotropic receptors can stimulate Ca2+ influx directly via receptor-operated ion channels or indirectly through voltage-sensitive Ca2+ channels (VSCC), whereas metabotropic receptors are coupled to a G-protein-regulated phospholipase C (PLC). This enzyme generates the second messengers inositol 1,4,5- trisphosphate (InsP/3) and diacylglycerol (DAG), resulting mobilization of [Ca2+]/i and activation of protein kinase C (PKC), respectively. We will use the cerebellar granule cell as an in vitro model system to determine the effects of acute ethanol treatment on the expression of these EAA transmembrane signaling systems and their physiological functions in developing neurons of the cerebellum.
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