Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model.
Excessive astrocytosis in cortical tubers in tuberous sclerosis complex (TSC) suggests that astrocytes may be important for epileptogenesis in TSC. We previously demonstrated that astrocyte-specific Tsc1 gene inactivation in mice (Tsc1 cKO mice) results in progressive epilepsy. Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes. Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression. Electrophysiological assays demonstrate a functional decrease in glutamate transport currents of Tsc1 cKO astrocytes in hippocampal slices and astrocyte cultures. These findings suggest that Tsc1 inactivation in astrocytes causes dysfunctional glutamate homeostasis, leading to seizure development in TSC.
Wong
Michael
M
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Ess
Kevin C
KC
Uhlmann
Erik J
EJ
Jansen
Laura A
LA
Li
Wen
W
Crino
Peter B
PB
Mennerick
Steven
S
Yamada
Kelvin A
KA
Gutmann
David H
DH
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001693:Biological Transport, Active; D015153:Blotting, Western; D002478:Cells, Cultured; D004594:Electrophysiology; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000150:complications / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
D011506:Proteins; D012333:RNA, Messenger; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D018698:Glutamic Acid