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eNeuro. 2016 Jun 21;3(3). pii: ENEURO.0004-16.2016. doi: 10.1523/ENEURO.0004-16.2016. eCollection 2016 May-Jun.

Microglial Contact Prevents Excess Depolarization and Rescues Neurons from Excitotoxicity.

Author information

1
Divison of Homeostatic Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan; Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Nishigo-naka, Myodaiji-cho, Japan.
2
Divison of Homeostatic Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan; Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Nishigo-naka, Myodaiji-cho, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Saitama, Japan.
3
Divison of Homeostatic Development, National Institute for Physiological Sciences , Okazaki 444-8585, Japan.
4
Department of Physiology, School of Medical Sciences, University of New South Wales , Sydney 2052, New South Wales, Australia.
5
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts 02215.
6
Divison of Homeostatic Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan; Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Nishigo-naka, Myodaiji-cho, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.

Abstract

Microglia survey and directly contact neurons in both healthy and damaged brain, but the mechanisms and functional consequences of these contacts are not yet fully elucidated. Combining two-photon imaging and patch clamping, we have developed an acute experimental model for studying the role of microglia in CNS excitotoxicity induced by neuronal hyperactivity. Our model allows us to simultaneously examine the effects of repetitive supramaximal stimulation on axonal morphology, neuronal membrane potential, and microglial migration, using cortical brain slices from Iba-1 eGFP mice. We demonstrate that microglia exert an acute and highly localized neuroprotective action under conditions of neuronal hyperactivity. Evoking repetitive action potentials in individual layer 2/3 pyramidal neurons elicited swelling of axons, but not dendrites, which was accompanied by a large, sustained depolarization of soma membrane potential. Microglial processes migrated to these swollen axons in a mechanism involving both ATP and glutamate release via volume-activated anion channels. This migration was followed by intensive microglial wrapping of affected axons and, in some cases, the removal of axonal debris that induced a rapid soma membrane repolarization back to resting potentials. When the microglial migration was pharmacologically blocked, the activity-induced depolarization continued until cell death ensued, demonstrating that the microglia-axon contact served to prevent pathological depolarization of the soma and maintain neuronal viability. This is a novel aspect of microglia surveillance: detecting, wrapping, and rescuing neuronal soma from damage due to excessive activity.

KEYWORDS:

ATP release; axonal swelling; excitotoxicty; microglia; neuronal rescue

PMID:
27390772
PMCID:
PMC4916329
DOI:
10.1523/ENEURO.0004-16.2016
[Indexed for MEDLINE]
Free PMC Article

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