Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function. Academic Article uri icon

Overview

abstract

  • Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl- channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.

authors

  • Wu, Qianyi
  • Akhter, Azman
  • Pant, Shashank
  • Cho, Eunjoo
  • Zhu, Jin Xin
  • Garner, Alastair
  • Ohyama, Tomoko
  • Tajkhorshid, Emad
  • van Meyel, Donald J
  • Ryan, Renae M

publication date

  • April 1, 2022

Research

keywords

  • Ataxia
  • Drosophila melanogaster

Identity

PubMed Central ID

  • PMC8970671

Scopus Document Identifier

  • 85125947599

Digital Object Identifier (DOI)

  • 10.1002/pro.3943

PubMed ID

  • 35167492

Additional Document Info

volume

  • 132

issue

  • 7