Article
Involvement of neuronal phosphotyrosine signal adaptor N-Shc in the kainic acid-induced epileptiform activity
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Published: | June 4, 2012 |
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BDNF-TrkB signaling is implicated in experimental seizure and epilepsy. However, the downstream signaling mechanism of epileptogenesis from TrkB receptor activation is still controversial and whether it progresses through the PLCγ, Shc, or both is unclear. Recent studies have demonstrated that the so called PLCγ site, but not Shc site, plays an essential role in kindling development. However, it still remains unclear whether the Shc-mediated signaling pathway is exclusive to epileptiform activity and epileptogenesis. In the brain, signaling at the TrkB-Shc site, is transmitted through the neural-specific phosphotyrosine signal adaptor N-Shc. Therefore, the aim of this study is to examine whether N-Shc is involved in kainic acid (KA)-induced epileptiform activity. We show that pre-treating wild type mice with the TrkB inhibitor K252a significantly reduced the severity of KA-induced seizures, suggesting that TrkB-mediated signaling is crucial for the KA-induced seizure. Moreover, we show a significant reduction of both, the seizure scale and the frequency of epileptiform discharge, in the hippocampus of N-Shc deficient mice compared to the control mice. The KA-induced selective neuronal cell loss in the CA3 area of the hippocampus was also inhibited in the N-Shc deficient mice. These results suggest that N-Shc is essentially involved in the KA-induced epileptiform activity. We propose that the N-Shc-mediated signaling pathway would provide a potential target for the development of novel therapeutic drugs and/or approaches in the treatment of epilepsy.