Edward M. Lieberman - US grants

DESCRIPTION: (Adapted from Applicant's Abstract): The objective of the proposed study is to clarify the conserved mechanisms and functional significance of axon glial signaling. Excitation of invertebrate and vertebrate nerve fibers activates synaptic and non-synaptic release of glutamate. At non-synaptic sites, glutamate produces second messenger changes and calcium waves that are proposed to maintain potassium homeostasis for preservation of neuronal excitability, and to influence nerve tissue metabolism, growth, and differentiation. The implication of these studies is that one can no longer think of transmitters as being used for synaptic communication alone but one must consider that the action potential propagating down the axon releases a transmitter agent that modulates the responses of all or most cells in the proximity of its path. An important clinical implication of this concept is that pathological conditions of the nervous system (for example stroke, mechanical head trauma, epilepsy, ischemia) in which glutamate potassium accumulate abnormally in the extracelluar space may disrupt functions both synaptically and non-synaptically and lead to cellular death. This is the first systematic study in any intact nervous system of 1) the kinetics, ion, and action potential-dependence of the release glutamate from nerve fibers, 2) the properties of glial and axonal glutamate transport mechanism relevant to glutamate release from axons and 3) the contribution of glia to metabolism of releasable glutamate. Excitation-induced release of exogenous and endogenous glutamate from nerve fibers will be assessed by electrophoretic and chromatographic assays. Ion substitution, ion channel blocker, and glutamate transport inhibitors will be used to delineate the properties of the release process and to distinguish among the possible