The unifying theme of this program project is a cellular and molecular approach to developmental neurology in an attempt to uncover processes leading to neonatal brain injury and mental retardation. Three inter- related projects are planned. They all concern calcium-dependent phenomena involving the influence of growth factors and/or excitatory neurotransmitters on neuronal outgrowth and survival. A multi-disciplinary approach is planned using molecular, neurophysiologic, pharmacologic, and morphologic techniques in both cell culture and whole-animal experiments. Project I concerns sequential patch-clamp recording and polymerase chain reaction (PCR) on a single central neuron. This new technique allows one to record the electrical currents of single channels in a cell with a patch electrode, suck the MRNA of that cell into the patch electrode, and then probe for the message that encodes the channels underlying the electrical signal in the same cell using PCR. Calcium-permeable, excitatory transmitter-gated channels (regulated by nicotinic and glutamatergic receptors) are being investigated in this manner. Projects II and III will use clinically safe antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor to combat neurotoxicity in tissue culture and whole- animal models of a variety of neurological disorders including hypoxic- ischemic brain injury, trauma, seizures, and various neurodegenerative diseases such as the neurological manifestations of AIDS. These novel NMDA antagonists have been developed in the preliminary studies of this project and include;(i) amantadine derivatives that produce open-channel block, and (ii) substances that generate nitric oxide or glutathione to affect the redox modulatory site of the NMDA receptor-channel complex. In addition, Project III explores an underlying mechanism of HIV-related neuron and oligodendrocyte/myelin injury by investigating the possible role of the envelope protein gp 120 and macrophage toxic factors in tissue culture systems of rodent and human cells and also in a rat pup model. These basic studies may lead to further information on the possible treatment of a variety of developmental disorders which contribute to the etiology of mental retardation, including hypoxic-ischemic brain injury and the neurological manifestations of AIDS in neonates and children.
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