Samarasinghe Ranmal A, Kanuparthi Prasad S, Timothy Greenamyre J, DeFranco Donald B, Di Maio Roberto
University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, USA; University of California Los Angeles, Department of Neurology, USA.
University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, USA.
Neurobiol Dis. 2014 Oct;70:252-61. doi: 10.1016/j.nbd.2014.06.020. Epub 2014 Jul 6.
While aberrant cell proliferation and differentiation may contribute to epileptogenesis, the mechanisms linking an initial epileptic insult to subsequent changes in cell fate remain elusive. Using both mouse and human iPSC-derived neural progenitor/stem cells (NPSCs), we found that a combined transient muscarinic and mGluR1 stimulation inhibited overall neurogenesis but enhanced NPSC differentiation into immature GABAergic cells. If treated NPSCs were further passaged, they retained a nearly identical phenotype upon differentiation. A similar profusion of immature GABAergic cells was seen in rats with pilocarpine-induced chronic epilepsy. Furthermore, live cell imaging revealed abnormal de-synchrony of Ca(++) transients and altered gap junction intercellular communication following combined muscarinic/glutamatergic stimulation, which was associated with either acute site-specific dephosphorylation of connexin 43 or a long-term enhancement of its degradation. Therefore, epileptogenic stimuli can trigger acute and persistent changes in cell fate by altering distinct mechanisms that function to maintain appropriate intercellular communication between coupled NPSCs.
虽然异常的细胞增殖和分化可能促成癫痫发生，但将最初的癫痫损伤与随后的细胞命运变化联系起来的机制仍不清楚。利用小鼠和人诱导多能干细胞衍生的神经祖细胞/干细胞（NPSC），我们发现毒蕈碱和代谢型谷氨酸受体1（mGluR1）联合短暂刺激会抑制整体神经发生，但会增强NPSC向未成熟GABA能细胞的分化。如果对处理过的NPSC进一步传代，它们在分化时会保留几乎相同的表型。在毛果芸香碱诱导的慢性癫痫大鼠中也观察到类似大量的未成熟GABA能细胞。此外，活细胞成像显示，毒蕈碱/谷氨酸能联合刺激后，Ca(++)瞬变出现异常去同步化，间隙连接细胞间通讯改变，这与连接蛋白43的急性位点特异性去磷酸化或其降解的长期增强有关。因此，致痫刺激可通过改变维持耦合NPSC之间适当细胞间通讯的不同机制，触发细胞命运的急性和持续性变化。
