Authors :
Presenting Author: Xin Tang, PhD – Boston Children's Hospital
Tenzin Lungjangwa, MS – Whitehead Institute; Qian Ren, PhD – Postdoc fellow, Neurosurgery, Boston Children's Hospital; Stephen Moss, PhD – Professor, Tufts University Medical School
Rationale:
Neural network hyperexcitability caused by impairments in GABAergic inhibition gives raise to epilepsy that affects 3.4 million patients in the US. KCC2 is a neuronal chloride transporter critical for the inhibitory action of GABA. Pathogenic KCC2 variants have been discovered in epilepsy patients but their functional significance and drug responsiveness are largely unknown.
Methods:
To gain insight into the molecular mechanisms through which KCC2 mutants cause neural dysfunction, we investigated KCC2 mutant phenotypes in human stem cell-derived neurons carrying KCC2 mutations, and in a mouse model that expresses mutant KCC2
in vivo. We will further investigate whether KCC2 mutant phenotypes can be rescued by treatment with drugs recently discovered in our team that stimulate KCC2 expression or activity.
Results:
Our results indicate that the mutant KCC2 proteins show impairments in stability and membrane insertion, which results in disrupted GABAergic inhibition that leads to epilepsy-like network hyperexcitability in human neurons and in the mouse brain.
Conclusions:
Our research established the functional role of KCC2 mutants in the epileptic brain and demonstrate the efficacy of KCC2-targeting drugs in suppressing hyperexcitability, laying the foundation for a novel therapeutic avenue to modify epilepsy disease process.
Funding:
Simons Foundation Autism Research Initiative (SFARI) Bridge to Independence Career Transition Award to X.T. Charles H. Hood Foundation Child Health Research Award to X.T.