Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China.
Cell Rep. 2023 Oct 31;42(10):113202. doi: 10.1016/j.celrep.2023.113202. Epub 2023 Sep 30.
CDKL5 deficiency disorder (CDD) is a severe epileptic encephalopathy resulting from pathological mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. Despite significant progress in understanding the neuronal function of CDKL5, the molecular mechanisms underlying CDD-associated epileptogenesis are unknown. Here, we report that acute ablation of CDKL5 from adult forebrain glutamatergic neurons leads to elevated neural network activity in the dentate gyrus and the occurrence of early-onset spontaneous seizures via tropomyosin-related kinase B (TrkB) signaling. We observe increased expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of its receptor TrkB in the hippocampus of Cdkl5-deficient mice prior to the onset of behavioral seizures. Moreover, reducing TrkB signaling in these mice rescues the altered synaptic activity and suppresses recurrent seizures. These results suggest that TrkB signaling mediates epileptogenesis in a mouse model of CDD and that targeting this pathway might be effective for treating epilepsy in patients affected by CDKL5 mutations.
CDKL5 缺乏症（CDD）是一种严重的癫痫性脑病，由 X 连锁周期素依赖性激酶样 5（CDKL5）基因突变引起。尽管人们对 CDKL5 的神经元功能有了深入的了解，但与 CDD 相关的癫痫发生的分子机制尚不清楚。在这里，我们报告说，急性敲除成年大脑谷氨酸能神经元中的 CDKL5 会通过原肌球蛋白相关激酶 B（TrkB）信号导致齿状回的神经网络活动升高，并发生早发性自发性癫痫发作。我们观察到在行为性癫痫发作之前，Cdkl5 缺陷型小鼠的海马体中脑源性神经营养因子（BDNF）的表达增加，其受体 TrkB 的活性增强。此外，在这些小鼠中降低 TrkB 信号可挽救改变的突触活性并抑制复发性癫痫发作。这些结果表明，TrkB 信号在 CDD 的小鼠模型中介导癫痫发生，并且靶向该途径可能对治疗受 CDKL5 突变影响的患者的癫痫有效。
