State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signaling in neurosecretory neurons

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 <i>in vitro</i> and <i>in vivo</i> 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.

Name thesis:degree_name

MS

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Pharmacy: Pharmaceutical Sciences

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Fleming, Tiffany M.

Contributors dc:contributor

• Gudelsky, Gary

• Pharmaceuticals
• astrocyte
• NMDA
• plasticity
• extrasynaptic
• neuroendocrine
• vasopressin

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352490527

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1352490527