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Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures.


ABSTRACT: 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.

SUBMITTER: Moore YE 

PROVIDER: S-EPMC6176565 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures.

Moore Yvonne E YE   Deeb Tarek Z TZ   Chadchankar Heramb H   Brandon Nicholas J NJ   Moss Stephen J SJ  

Proceedings of the National Academy of Sciences of the United States of America 20180917 40


The type 2 K<sup>+</sup>/Cl<sup>-</sup> cotransporter (KCC2) allows neurons to maintain low intracellular levels of Cl<sup>-</sup>, 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 preven  ...[more]

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