Despite the long-established presence of glutamate NMDA receptors at extrasynaptic sites (eNMDARs), their functional roles remain poorly understood. Factors influencing the concentration and time course of glutamate in the extrasynaptic space, such as the topography of the neuronal-glial microenvironment, as well as glial glutamate transporters, are expected to affect eNMDAR-mediated signalling strength. In this study, we used in vitro and in vivo electrophysiological recordings to assess the properties, functional relevance and modulation of a persistent excitatory current mediated by activation of eNMDARs in hypothalamic supraoptic nucleus (SON) neurons. We found that extracellular glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic INMDA), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin a-aminodadipic acid, enhanced tonic INMDA and neuronal activity, supporting an astrocyte regulation of tonic INMDA strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodeling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic INMDA strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic INMDA activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge.
|Commitee:||Gregerson, Karen, Richards, David|
|School:||University of Cincinnati|
|School Location:||United States -- Ohio|
|Source:||MAI 51/05M(E), Masters Abstracts International|
|Subjects:||Neurosciences, Pharmacy sciences, Physiology|
|Keywords:||Astrocyte, Extrasynaptic, Neuroendocrine, Nmda, Plasticity, Vasopressin|
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