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

PLoS One. 2015 Oct 16;10(10):e0140324. doi: 10.1371/journal.pone.0140324. eCollection 2015.

Abstract

Background: Acidosis 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.

Results: Experiments 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.

Conclusion: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis* / metabolism
  • Acidosis* / pathology
  • Acidosis* / physiopathology
  • Animals
  • Brain Diseases, Metabolic* / metabolism
  • Brain Diseases, Metabolic* / pathology
  • Brain Diseases, Metabolic* / physiopathology
  • Cerebral Cortex* / metabolism
  • Cerebral Cortex* / pathology
  • GABAergic Neurons* / metabolism
  • GABAergic Neurons* / pathology
  • Mice
  • Mice, Transgenic
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate

Grant support

This study is supported by National Basic Research Program (2013CB531304 and 2011CB504405) and Natural Science Foundation China (30990261, 81171033 and 81471123) to JHW, as well as Anhui Natural Science Foundation (1308085QH147) to LH and (1408085MH185) to SDZ.