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

Tiffany M. Fleming, Victoria Scott, Krishna Naskar, Natalie Joe, Colin H. Brown, Javier Eduardo Stern

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3929-3941
Number of pages13
JournalJournal of Physiology
Volume589
Issue number16
DOIs
StatePublished - Aug 1 2011

Fingerprint

N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Astrocytes
Supraoptic Nucleus
Neurons
Neuroglia
Amino Acid Transport System X-AG
Glutamic Acid
Gliotoxin
Glutamate Receptors
Dehydration
Pharmacology
Acids

ASJC Scopus subject areas

  • Physiology

Cite this

State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons. / Fleming, Tiffany M.; Scott, Victoria; Naskar, Krishna; Joe, Natalie; Brown, Colin H.; Stern, Javier Eduardo.

In: Journal of Physiology, Vol. 589, No. 16, 01.08.2011, p. 3929-3941.

Research output: Contribution to journalArticle

Fleming, Tiffany M. ; Scott, Victoria ; Naskar, Krishna ; Joe, Natalie ; Brown, Colin H. ; Stern, Javier Eduardo. / State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons. In: Journal of Physiology. 2011 ; Vol. 589, No. 16. pp. 3929-3941.
@article{1e040386574f46568731be4b6bc07d41,
title = "State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons",
abstract = "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.",
author = "Fleming, {Tiffany M.} and Victoria Scott and Krishna Naskar and Natalie Joe and Brown, {Colin H.} and Stern, {Javier Eduardo}",
year = "2011",
month = "8",
day = "1",
doi = "10.1113/jphysiol.2011.207340",
language = "English (US)",
volume = "589",
pages = "3929--3941",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "16",

}

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 Eduardo

PY - 2011/8/1

Y1 - 2011/8/1

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.

UR - http://www.scopus.com/inward/record.url?scp=80051661227&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051661227&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2011.207340

DO - 10.1113/jphysiol.2011.207340

M3 - Article

C2 - 21690192

AN - SCOPUS:80051661227

VL - 589

SP - 3929

EP - 3941

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 16

ER -