Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability

ABSTRACT

Introduction

Epilepsy is a common neurological disorder of neuronal hyperexcitability that begets recurrent and unprovoked seizures. The lack of a truly satisfactory pharmacotherapy for epilepsy highlights the clinical urgency for the discovery of new drug targets. To that end, targeting the electroneutral K⁺/Cl⁻ cotransporter KCC2 has emerged as a novel therapeutic strategy for the treatment of epilepsy.

Areas covered

We summarize the roles of KCC2 in the maintenance of synaptic inhibition and the evidence linking KCC2 dysfunction to epileptogenesis. We also discuss preclinical proof-of-principle studies that demonstrate that augmentation of KCC2 function can reduce seizure activity. Moreover, potential strategies to modulate KCC2 activity for therapeutic benefit are highlighted.

Expert opinion

Although KCC2 is a promising drug target, questions remain before clinical translation. It is unclear whether increasing KCC2 activity can reverse epileptogenesis, the ultimate curative goal for epilepsy therapy that extends beyond seizure reduction. Furthermore, the potential adverse effects associated with increased KCC2 function have not been studied. Continued investigations into the neurobiology of KCC2 will help to translate promising preclinical insights into viable therapeutic avenues that leverage fundamental properties of KCC2 to treat medically intractable epilepsy and other disorders of failed synaptic inhibition with attendant neuronal hyperexcitability.

KEYWORDS:

• Epilepsy
• seizure
• antiepileptic drugs
• KCC2
• chloride Homeostasis
• GABA
• neuronal hyperexcitability

Article highlights

• Deranged neuronal excitability underlies epilepsy, a difficult-to-treat neurological disorder with profound need for better pharmacotherapy

• The electroneutral K⁺/Cl⁻ cotransporter KCC2 regulates neuronal excitability by regulation of chloride homeostasis and gamma-aminobutyric acid-ergic (GABAergic) inhibition

• KCC2 dysfunction and attendant impairments in Cl⁻ extrusion from neurons is linked to epileptogenesis in humans, while augmenting KCC2 function confers an anticonvulsant effect in preclinical models

• Pharmacological strategies to increase KCC2 function include KCC2 agonism and targeting of the upstream with-no-lysine kinase (WNK)/Ste20-related proline-alanine kinase (SPAK)

• KCC2 is a promising drug target for the treatment of epilepsy and other disorders of neuronal hyperexcitability

This box summarizes key points contained in the article.

Declaration of interest

Z. He’s lab received a sponsored research project from Axonis.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors was supported by 1R01NS109358-01 (to KK), 1R01NS111029-01A1 (to KK), 1R01NS110850 (to ZH), the Simons Foundation (to KK), the March of Dimes Foundation (to KK), and National Institutes of Health (NIH) Medical Scientist Program Training Grant T32GM007205 (to PQD).