TY - JOUR
T1 - State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons
AU - Fleming, Tiffany M.
AU - Scott, Victoria
AU - Naskar, Krishna
AU - Joe, Natalie
AU - Brown, Colin H.
AU - Stern, Javier E.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/8
Y1 - 2011/8
N2 - 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 ambient glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic I NMDA), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin α-aminodadipic acid, enhanced tonic I NMDA and neuronal activity, supporting an astrocyte regulation of tonic I NMDA strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodelling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic I NMDA strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic I NMDA activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge.
AB - 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 ambient glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic I NMDA), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin α-aminodadipic acid, enhanced tonic I NMDA and neuronal activity, supporting an astrocyte regulation of tonic I NMDA strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodelling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic I NMDA strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic I NMDA activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge.
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U2 - 10.1113/jphysiol.2011.207340
DO - 10.1113/jphysiol.2011.207340
M3 - Article
C2 - 21690192
AN - SCOPUS:80051661227
SN - 0022-3751
VL - 589
SP - 3929
EP - 3941
JO - Journal of Physiology
JF - Journal of Physiology
IS - 16
ER -