Impaired axon initial segment structure and function in a model of ARHGEF9 developmental and epileptic encephalopathy

• 成果类型: Article
• 署名作者: Wang, Wanqi; Williams, Damian J.; Teoh, Jia Jie; Soundararajan, Divyalakshmi; Zuberi, Aamir; Lutz, Cathleen M.; Frankel, Wayne N.; Makinson, Christopher D.
• 署名单位: NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Columbia University; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Jackson Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14872
• DOI: 10.1073/pnas.2400709121
• 发表日期: 2024-10-15
• 关键词: action-potential initiation; inhibitory synapses; collybistin; gephyrin; plasticity; transmission; maintenance; na(v)1.6; neurons; mutant

摘要

Developmental and epileptic encephalopathies (DEE) are rare but devastating and largely intractable childhood epilepsies. Genetic variants in ARHGEF9, encoding a scaffolding protein important for the organization of the postsynaptic density of inhibitory synapses, are associated with DEE accompanied by complex neurological phenotypes. In a mouse model carrying a patient- derived ARHGEF9 variant associated with severe disease, we observed aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo- axonic synaptic inhibition, disrupted action potential generation, and complex seizure phenotypes consistent with clinical observations. These results illustrate diverse roles of ARHGEF9 that converge on regulation of the structure and function of the AIS, thus revealing a pathological mechanism for ARHGEF9- associated DEE. This unique example of a neuropathological condition associated with multiple AIS dysfunctions may inform strategies for treating neurodevelopmental diseases.