CDKL5 deficiency in adult glutamatergic neurons alters synaptic activity and causes spontaneous seizures via TrkB signaling
Zi-Ai Zhu,
Yi-Yan Li,
Juan Xu,
Hui Xue,
Xue Feng,
Yong-Chuan Zhu,
Zhi-Qi Xiong
Affiliations
Zi-Ai Zhu
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
Yi-Yan Li
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
Juan Xu
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China
Hui Xue
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
Xue Feng
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China
Yong-Chuan Zhu
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Corresponding author
Zhi-Qi Xiong
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; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding author
Summary: 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.
