| Authors |
McKenzie, Chaseley E ; Aung, Khaing Phyu ; Dos Santos, Altair Brito ; Mao, Miaomiao ; Spyrou, James ; Bryson, Alexander ; Wong, Raymond ; Lin, Susan X N ; Bleakley, Lauren E ; Palmqvist, Joakim ; Guzulaitis, Robertas ; Kan, Anthony S H ; Liao, Vivian W Y ; Soh, Ming S ; Gomez, Carlos Daniel ; Larsen, Victor ; Petersen, Anne Marie Nordvig ; Absalom, Nathan L ; Møller, Rikke S ; Chebib, Mary ; Perrier, Jean-François ; Ahring, Philip K ; Reid, Christopher A |
| Abstract [eng] |
Gain-of-function (GOF) variants in GABAA receptors are increasingly recognised as a cause of severe developmental and epileptic encephalopathies (DEE). However, the mechanisms by which enhanced GABAA receptor activity leads to neuronal network hyperexcitability remains unclear. We engineered a novel mouse model based on the human GOF GABRB3 p.(Glu77Lys) variant (β3E77K), identified in two individuals diagnosed with DEE, to explore the mechanisms underlying GABAA receptor GOF disease. The phenotypes of β3E77K mice included embryonic lethality consistent with a severe early developmental impact of the GOF GABAA receptor variant. These mice display spike-wave-like discharges that were exacerbated by vigabatrin and ameliorated by valproate matching the clinical observations of GOF GABRB3 patients. β3E77K mice also have increased proconvulsant-induced seizure susceptibility and a broad increase in ECoG spectral power amplitude, indicative of cortical hyperexcitability. Additionally, neurological assessments revealed hypoactivity and weakened grip-strength. |
