MGluR5 protect astrocytes from ischemic damage in postnatal CNS white matter

Ilaria Vanzulli,Arthur M Butt

doi:10.1016/j.ceca.2015.06.010

Abstract

Astrocytes perform essential neuron-supporting functions in the central nervous system (CNS) and their disruption has devastating effects on neuronal integrity in multiple neuropathologies. Although astrocytes are considered resistant to most pathological insults, ischemia can result in astrocyte injury and astrocytes in postnatal white matter are particularly vulnerable. Metabotropic glutamate receptors (mGluR) are neuroprotective in ischemia and are widely expressed by astrocytes throughout CNS grey matter, but their potential cytoprotective role in astrocytes had not been determined. Here, we identify functional expression of group I mGluR in white matter astrocytes and demonstrate their activation protects astrocytes from ischemic damage in the postnatal mouse optic nerve. Optic nerve astrocytes are shown to express mGluR5 using immunolabelling of sections and explant cultures from transgenic reporter mice in which GFAP drives expression of EGFP. In addition, using Fluo-4 calcium imaging in isolated intact optic nerves, we show that the group I/II mGluR agonist ACPD and the specific group I mGluR agonist DHPG evoke glial Ca2+ signals that were significantly inhibited by the group I mGluR antagonist AIDA. A key finding is that activation of group I mGluR protects astrocytes against oxygen-glucose deprivation (OGD) in situ, in isolated intact optic nerves from GFAP-EGFP mice. This study identifies a role for group I mGluR in protecting astrocytes against ischemia in postnatal white matter and suggests this may be a strategy for limiting damage in neuropathologies involving excitotoxity.

Highlights

Astrocytes have diverse and important functions in the pathology of cerebral ischemia [1]
Glutamatergic signaling is prominent in white matter, astroglial expression of Metabotropic glutamate receptors (mGluR) was unresolved, and so we examined this in transgenic GFAP-EGFP reporter mice
Similar punctate mGluR5 immunolabelling was observed in optic nerve sections (Fig. 1E), some of which colocalized to GFAP-EGFP+ astrocytes (Fig. 1D and G)

Summary

Introduction

Astrocytes have diverse and important functions in the pathology of cerebral ischemia [1]. Astrocytes may be less susceptible than neurons to ischemic damage, astrocyte death is an important component of ischemia and has detrimental effects on neuronal survival and integrity [2,3,4,5]. The susceptibility of astrocytes to ischemia depends on the brain region [6], and astrocytes in developing white matter may be vulnerable [5,7,8]. Glutamate is central to white matter pathology [9,10], and is excitoxic for astrocytes in vitro [11] and in situ in the spinal cord [12].

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Results

Conclusion