Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Neurobiol Dis. 2010 Mar;37(3):764-71. doi: 10.1016/j.nbd.2009.12.020. Epub 2010 Jan 4.
Astrocyte dysfunction may contribute to epileptogenesis and other neurological deficits in Tuberous Sclerosis Complex (TSC). In particular, decreased expression and function of astrocyte glutamate transporters have been implicated in causing elevated extracellular glutamate levels, neuronal death, and epilepsy in a mouse model of TSC (Tsc1(GFAP)CKO mice), involving inactivation of the Tsc1 gene primarily in astrocytes. Here, we tested whether pharmacological induction of astrocyte glutamate transporter expression can prevent the neurological phenotype of Tsc1(GFAP)CKO mice. Early treatment with ceftriaxone prior to the onset of epilepsy increased expression of astrocyte glutamate transporters, decreased extracellular glutamate levels, neuronal death, and seizure frequency, and improved survival in Tsc1(GFAP)CKO mice. In contrast, late treatment with ceftriaxone after onset of epilepsy increased glutamate transporter expression, but had no effect on seizures. These results indicate that astrocyte glutamate transporters contribute to epileptogenesis in Tsc1(GFAP)CKO mice and suggest novel therapeutic strategies for epilepsy in TSC directed at astrocytes.
星形胶质细胞功能障碍可能导致结节性硬化症 (TSC) 中的癫痫发生和其他神经缺陷。特别是，星形胶质细胞谷氨酸转运体表达和功能的降低与引起细胞外谷氨酸水平升高、神经元死亡和癫痫有关，这在 TSC 的小鼠模型（Tsc1(GFAP)CKO 小鼠）中已经得到证实，主要涉及星形胶质细胞中 Tsc1 基因的失活。在这里，我们测试了是否可以通过诱导星形胶质细胞谷氨酸转运体的表达来预防 Tsc1(GFAP)CKO 小鼠的神经表型。在癫痫发作前早期用头孢曲松治疗可增加星形胶质细胞谷氨酸转运体的表达，降低细胞外谷氨酸水平、神经元死亡和癫痫发作频率，并改善 Tsc1(GFAP)CKO 小鼠的存活率。相比之下，癫痫发作后晚期用头孢曲松治疗可增加谷氨酸转运体的表达，但对癫痫发作没有影响。这些结果表明，星形胶质细胞谷氨酸转运体在 Tsc1(GFAP)CKO 小鼠的癫痫发生中起作用，并为 TSC 中的癫痫提出了针对星形胶质细胞的新的治疗策略。
