Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity.

Li Huang,Jin-Hui Wang,Sudong Guan,Wei Lu,Yan Zhu,Shidi Zhao,Anuja Ghorpade

doi:10.1371/journal.pone.0140324

Abstract

BackgroundAcidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury.ResultsExperiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons.ConclusionOur studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously.

Highlights

Acidosis, a base-acid imbalance, is associated with many diseases in the clinic practices including diabetes mellitus as well as the disorders in the urinary, respiratory and gastrointestinal systems [1,2,3,4]
To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly
Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis

Summary

Introduction

A base-acid imbalance, is associated with many diseases in the clinic practices including diabetes mellitus as well as the disorders in the urinary, respiratory and gastrointestinal systems [1,2,3,4]. Previous studies focused on elucidating a role of metabolic alternations in neuron dysfunction, including intracellular enzyme activities [6], proton accumulation [7,8], acid-sensing ion channels [9,10,11,12,13,14], voltage-gated sodium channels [15] and voltagegated calcium channels [16]. How these mechanisms occur in the specific types of the neurons and glia cells for acidosis-induced neuropathy is largely unknown. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury

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