Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6
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Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6. / Kovermann, Peter; Untiet, Verena; Kolobkova, Yulia; Engels, Miriam; Baader, Stephan; Schilling, Karl; Fahlke, Christoph.
In: Brain Communications, Vol. 2, No. 1, 22, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6
AU - Kovermann, Peter
AU - Untiet, Verena
AU - Kolobkova, Yulia
AU - Engels, Miriam
AU - Baader, Stephan
AU - Schilling, Karl
AU - Fahlke, Christoph
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - glutamate transporters
KW - chloride homeostasis
KW - Bergmann glia
KW - glial apoptosis
KW - episodic ataxia
KW - ACTIVE CASPASE-3 EXPRESSION
KW - CEREBELLAR PURKINJE-CELLS
KW - MOUSE MODEL
KW - SYNAPTIC INHIBITION
KW - CLIMBING FIBERS
KW - RAT CEREBELLUM
KW - IN-VIVO
KW - MUTATION
KW - HETEROGENEITY
KW - MODULATION
U2 - 10.1093/braincomms/fcaa022
DO - 10.1093/braincomms/fcaa022
M3 - Journal article
C2 - 32954283
VL - 2
JO - Brain Communications
JF - Brain Communications
SN - 2632-1297
IS - 1
M1 - 22
ER -
ID: 250112555