2025-07-21 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202507/t20250721_1047743.shtml
- https://www.pnas.org/doi/10.1073/pnas.2426375122
ZC4H2関連希少疾患の病因因子は、シナプス活動と認知機能のポストシナプス調節因子である The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function
Li Pear Wan, Yuwei Li, Shuhua Zhao, +8 , and Pengcheng Ma
Proceedings of the National Academy of Sciences Published:July 9, 2025
DOI:https://doi.org/10.1073/pnas.2426375122
Significance
Intellectual disability represents a core clinical manifestation of ZC4H2-associated rare disorder (ZARD), yet the underlying synaptic etiology remains elusive. In this study, with a conditional knockout mouse model depleting its pathogenic factor ZC4H2 in forebrain pyramidal neurons, we find that ZC4H2 is a postsynaptic regulator for AMPA receptors stability and excitatory synaptic activity, thereby playing essential roles in brain cognitive function. Notably, administration of perampanel, a clinical approved AMPA receptor-specific antagonist, successfully rescues synaptic dysregulation and cognitive malfunction of this disease model. These findings determine a physiological role of ZC4H2 in regulating excitatory synaptic activity and uncover synaptic dysfunction as a key mechanism driving ZARD-related intellectual disability, offering a targeted therapeutic avenue for cognitive impairment.
Abstract
The maintenance of excitatory synaptic activity is crucial for cognitive function and genetic mutations are responsible for the pathogenesis of related brain disorders. However, the roles of these pathogenic factors in synaptic dysregulation and cognitive malfunction are still poorly understood. In this study, a conditional knockout mouse model lacking ZC4H2—an X-linked gene implicated in ZC4H2-associated rare disorder (ZARD) —in forebrain excitatory neurons is generated and these mice exhibit cognitive malfunction, recapitulating the intellectual disability manifestation of ZARD. Mechanistically, ZC4H2 harbors a protein interaction network with key excitatory synaptic regulators and ZC4H2 interacts directly with AMPA receptors (AMPARs) and regulates their ubiquitination at the postsynaptic sites, thereby maintaining AMPARs protein stability and synaptic expression. ZC4H2 deficiency specifically and aberrantly increases AMPAR-mediated excitatory synaptic transmission and impairs synaptic plasticity of long-term potentiation. More importantly, pharmacological treatment with perampanel, an AMPAR-specific antagonist, successfully restores the excitatory synaptic activity and cognitive function of ZC4H2-deficient mice. Together, we establish that ZC4H2 is a postsynaptic regulator for AMPARs and excitatory synaptic activity and highlight that the dysregulation of these biological processes is a crucial etiology underlying ZARD-associated intellectual disability.
