| First Author | Moore YE | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 40 | Pages | 10166-10171 |
| PubMed ID | 30224498 | Mgi Jnum | J:265906 |
| Mgi Id | MGI:6201665 | Doi | 10.1073/pnas.1810134115 |
| Citation | Moore YE, et al. (2018) Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures. Proc Natl Acad Sci U S A 115(40):10166-10171 |
| abstractText | The type 2 K(+)/Cl(-) cotransporter (KCC2) allows neurons to maintain low intracellular levels of Cl(-), a prerequisite for efficient synaptic inhibition. Reductions in KCC2 activity are evident in epilepsy; however, whether these deficits directly contribute to the underlying pathophysiology remains controversial. To address this issue, we created knock-in mice in which threonines 906 and 1007 within KCC2 have been mutated to alanines (KCC2-T906A/T1007A), which prevents its phospho-dependent inactivation. The respective mice appeared normal and did not show any overt phenotypes, and basal neuronal excitability was unaffected. KCC2-T906A/T1007A mice exhibited increased basal neuronal Cl(-) extrusion, without altering total or plasma membrane accumulation of KCC2. Critically, activity-induced deficits in synaptic inhibition were reduced in the mutant mice. Consistent with this, enhanced KCC2 was sufficient to limit chemoconvulsant-induced epileptiform activity. Furthermore, this increase in KCC2 function mitigated induction of aberrant high-frequency activity during seizures, highlighting depolarizing GABA as a key contributor to the pathological neuronal synchronization seen in epilepsy. Thus, our results demonstrate that potentiating KCC2 represents a therapeutic strategy to alleviate seizures. |
