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Epileptogenesis and Reduced Inward Rectifier Potassium Current in Tuberous Sclerosis Complex‐1–Deficient Astrocytes
Author(s) -
Jansen Laura A.,
Uhlmann Erik J.,
Crino Peter B.,
Gutmann David H.,
Wong Michael
Publication year - 2005
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2005.00289.x
Subject(s) - epileptogenesis , tsc1 , inward rectifier potassium ion channel , tuberous sclerosis , chemistry , glial fibrillary acidic protein , astrocyte , neocortex , potassium channel , microbiology and biotechnology , neuroscience , biology , hippocampal formation , pi3k/akt/mtor pathway , endocrinology , ion channel , biochemistry , immunology , central nervous system , pathology , receptor , medicine , signal transduction , immunohistochemistry
Summary: Purpose: Individuals with tuberous sclerosis complex (TSC) frequently have intractable epilepsy. To gain insights into mechanisms of epileptogenesis in TSC, we previously developed a mouse model of TSC with conditional inactivation of the Tsc1 gene in glia ( Tsc1 GFAP CKO mice). These mice develop progressive seizures, suggesting that glial dysfunction may be involved in epileptogenesis in TSC. Here, we investigated the hypothesis that impairment of potassium uptake through astrocyte inward rectifier potassium (Kir) channels may contribute to epileptogenesis in Tsc1 GFAP CKO mice. Methods: Kir channel function and expression were examined in cultured Tsc1 ‐deficient astrocytes. Kir mRNA expression was analyzed in astrocytes microdissected from neocortical sections of Tsc1 GFAP CKO mice. Physiological assays of astrocyte Kir currents and susceptibility to epileptiform activity induced by increased extracellular potassium were further studied in situ in hippocampal slices. Results: Cultured Tsc1 ‐deficient astrocytes exhibited reduced Kir currents and decreased expression of specific Kir channel protein subunits, Kir2.1 and Kir6.1. mRNA expression of the same Kir subunits also was reduced in astrocytes from neocortex of Tsc1 GFAP CKO mice. By using pharmacologic modulators of signalling pathways implicated in TSC, we showed that the impairment in Kir channel function was not affected by rapamycin inhibition of the mTOR/S6K pathway, but was reversed by decreasing CDK2 activity with roscovitine or retinoic acid. Last, hippocampal slices from Tsc1 GFAP CKO mice exhibited decreased astrocytic Kir currents, as well as increased susceptibility to potassium‐induced epileptiform activity. Conclusions: Impaired extracellular potassium uptake by astrocytes through Kir channels may contribute to neuronal hyperexcitability and epileptogenesis in a mouse model of TSC.