期刊
NEUROBIOLOGY OF DISEASE
卷 160, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105529
关键词
WWOX; Epilepsy; Electrophysiology; NMDA; Coupling
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2015-04487/UofT, 487230]
- Canadian Institute of Health Research (CIHR) [119603]
- European Research Council (ERC) [682118]
Loss of function mutations of the WWOX gene are associated with severe pediatric epileptic encephalopathy. Mouse models show that WWOX plays a crucial role in regulating neuronal excitability.
Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX to that hyperexcitability has yet to be investigated. Using a mouse model of neuronal Wwox-deletion that exhibit spontaneous seizures, in vitro whole-cell and field potential electrophysiological characterization identified spontaneous bursting activity in the neocortex, a marker of the underlying network hyperexcitability. Spectral analysis of the neocortical bursting events highlighted increased phase-amplitude coupling, and a propagation from layer II/III to layer V. These bursts were NMDAR and gap junction dependent. In layer II/III pyramidal neurons, Wwox knockout mice demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced, as compared to heterozygote and wild-type littermate controls. Furthermore, these neurons were depolarized and demonstrated increased action potential frequency, sag current, and post-inhibitory rebound. These findings suggest WWOX plays an essential role in balancing neocortical excitability and provide insight towards developing therapeutics for those suffering from WWOX disorders.
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