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

This title appears in the Scientific Report : 2020

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

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 a...

Personal Name(s):	Kovermann, Peter (Corresponding author)
	Untiet, Verena / Kolobkova, Yulia / Engels, Miriam / Baader, Stephan / Schilling, Karl / Fahlke, Christoph
Contributing Institute:	Zelluläre Biophysik; ICS-4
Published in:	Brain communications, 2 (2020) 1, S. fcaa022
Imprint:	[Großbritannien] Guarantors of Brain 2020
DOI:	10.1093/braincomms/fcaa022
PubMed ID:	32954283
Document Type:	Journal Article
Research Program:	Physical Basis of Diseases
Link:	Get full text OpenAccess OpenAccess OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1093/braincomms/fcaa022 in citations.
Please use the identifier: http://hdl.handle.net/2128/25180 in citations.

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.