9604862 Jeftinija Two of the most important excitatory neurotransmitters in the brain are the amino acids glutamate and aspartate. The effectiveness of information transfer within the brain depends on the release of these excitatory amino acids from neurons, the interaction of these amino acids with specific receptors on target cells, and the termination of these interactions by the uptake of glutamate and aspartate from the extracellular milieu. This latter function is accomplished by glial cells. However, recent in vitro studies have shown that glial cells can also release these excitatory amino acids when stimulated by specific neuroligands such as bradykinin, and in turn cause neurons to release their neurotransmitters. Neuroligand-stimulated glial release of glutamate and aspartate is receptor mediated and calcium dependent, resembling neurotransmitter release from neurons. Glia may thus be far more important for normal brain function than previously imagined, and may even serve to convey information in the nervous system, a role previously reserved for neurons. The main objective of this proposal is to determine how glial cells actually release glutamate. There are three possible mechanisms: (i) neuroligand binding may cause reversal of the cross-membrane glutamate transporter which is know to be present in glial cells; (ii) neuroligand binding may cause glial swelling, which in turn might release glutamate through pores formed in the stretched cell wall; (iii) neuroligand binding may cause glutamate release by an exocytotic mechanism similar to that which neurons use to release glutamate and other neurotransmitters. It will be determine which of these possible mechanisms is responsible for neuroligand-stimulated release of glutamate from glial cells, studying isolated cultured glial cells as well as brain slice preparations in which glial cells maintain their relationships with surrounding cells. Understanding the mechanism of rel ease of excitatory amino acids from glial cells will allow us to elucidate the crucial roles of these cells in the transmission of information within the brain.
