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Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Peter Kovermann
  • Untiet, Verena
  • Yulia Kolobkova
  • Miriam Engels
  • Stephan Baader
  • Karl Schilling
  • Christoph Fahlke

Episodic ataxia type 6 is an inherited neurological condition characterized by combined ataxia and epilepsy. A severe form of this disease with episodes combining ataxia, epilepsy and hemiplegia was recently associated with a proline to arginine substitution at position 290 of the excitatory amino acid transporter 1 in a heterozygous patient. The excitatory amino acid transporter 1 is the predominant glial glutamate transporter in the cerebellum. However, this glutamate transporter also functions as an anion channel and earlier work in heterologous expression systems demonstrated that the mutation impairs the glutamate transport rate, while increasing channel activity. To understand how these changes cause ataxia, we developed a constitutive transgenic mouse model. Transgenic mice display epilepsy, ataxia and cerebellar atrophy and, thus, closely resemble the human disease. We observed increased glutamate-activated chloride efflux in Bergmann glia that triggers the apoptosis of these cells during infancy. The loss of Bergmann glia results in reduced glutamate uptake and impaired neural network formation in the cerebellar cortex. This study shows how gain-of-function of glutamate transporter-associated anion channels causes ataxia through modifying cerebellar development.

OriginalsprogEngelsk
Artikelnummer22
TidsskriftBrain Communications
Vol/bind2
Udgave nummer1
Antal sider17
ISSN2632-1297
DOI
StatusUdgivet - 2020
Eksternt udgivetJa

ID: 250112555