Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex.
Abnormalities in astrocytes occur in the brains of patients with Tuberous Sclerosis Complex (TSC) and may contribute to the pathogenesis of neurological dysfunction in this disease. Here, we report that knock-out mice with Tsc1 gene inactivation in glia (Tsc1(GFAP)CKO mice) exhibit decreased expression of the astrocytic connexin protein, Cx43, and an associated impairment in gap junction coupling between astrocytes. Correspondingly, hippocampal slices from Tsc1(GFAP)CKO mice have increased extracellular potassium concentration in response to stimulation. This impaired potassium buffering can be attributed to abnormal gap junction coupling, as a gap junction inhibitor elicits an additional increase in potassium concentration in control, but not Tsc1(GFAP)CKO slices. Furthermore, treatment with a mammalian target of rapamycin inhibitor reverses the deficient Cx43 expression and impaired potassium buffering. These findings suggest that Tsc1 inactivation in astrocytes causes defects in astrocytic gap junction coupling and potassium clearance, which may contribute to epilepsy in Tsc1(GFAP)CKO mice.
Xu
Lin
L
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zeng
Ling-Hui
LH
Wong
Michael
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology*; D017629:Gap Junctions / Q000378:metabolism*; D006624:Hippocampus / Q000503:physiopathology*; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D002352:Carrier Proteins; D018031:Connexin 43; D004791:Enzyme Inhibitors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D011188:Potassium