The long term objective of this research program is to understand the functions of the neuronal dipeptide, N-acetylaspartylglutamate (NAAG) in the mammalian visual system, particularly its role in retinogeniculate chemical neurotransmission. In the past it has proved difficult to identify high concentrations of any excitatory transmitter in retinal ganglion cells, the optic nerves, and their terminals, despite the fact that photic stimulation of the retina induces excitatory amino acid-like responses in postsynaptic target neurons. NAAG has been identified in the vast majority of retinal ganglion cells in all mammals studied, including humans. The highest concentration reported for NAAG in the CNS is in the optic chiasm, and its distribution indicates specific involvement in several stages of visual processing. NAAG also appears to be colocalized with classical transmitters, such as norepinephrine in the locus coeruleus, and this study will examine interactions between NAAG and other transmitters, derived from cortical and brainstem projections, acting at the level of the lateral geniculate nucleus. Because of its potential role in excitatory neurotransmission, this program also may have relevance to disorders of excitatory amino acid transmission, including excitotoxicity and seizure activity. Preliminary work has demonstrated that NAAG is localized in the ganglion and amacrine cells of the retina, in the optic axons, and in their terminals in all visual target zones in the rat. Utilizing immunohistochemistry and a highly specific RIA for soluble NAAG, large decreases in NAAG levels were detected in all visual target zones after optic nerve transections. Glutamate immunohistochemistry failed to demonstrate the presence of high levels of this amino acid in the optic projections, and no changes in glutamate immunoreactivity were noted in any visual target area after optic nerve transection. Based on its cellular distribution and synaptic release, a working hypothesis can be formulated that NAAG participates in chemical neurotransmission in the retinofugal pathways. To test this hypothesis the following specific aims are proposed: 1) determine the electrophysiological response of lateral geniculate neurons to NAAG; 2) ascertain the properties of NAAG metabolism in thalamic preparations with emphasis on defining the time course and extent of glutamate release from NAAG via extracellular hydrolysis; 3) employ dual- labeling immunohistochemistry to colocalize NAAG with other transmitters in retinal terminal zones; 4) establish whether second messenger responses to NAAG occur using a tissue slice preparation which include visual areas of thalamus; 5) determine the extent and degree of transynaptic changes in NAAG, NAA and glutamate levels in visual cortex following optic nerve transection.
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