Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• The K/Cl cotransporter KCC2 is crucial for neuronal chloride gradients and GABAergic signaling efficacy.
• Dysfunctional KCC2 contributes to epilepsy by causing depolarizing GABA signaling and pathological neuronal activity.
• Restoring chloride homeostasis via KCC2 enhancement is a potential therapeutic strategy for neurological disorders.

Purpose of the Study:

• To investigate the mechanisms by which prochlorperazine (PCPZ) and CLP-257 enhance KCC2 function.
• To evaluate the antiseizure effects of PCPZ and CLP-257 in preclinical epilepsy models.
• To provide evidence for the therapeutic potential of KCC2 enhancers in drug-resistant mesial temporal lobe epilepsy (mTLE).

Main Methods:

• Assessed KCC2 function, clustering, and membrane diffusion in cortical neurons treated with PCPZ and CLP-257.
• Measured GABA_A receptor-mediated currents to determine the impact of CLP-257 on synaptic and extrasynaptic currents.
• Utilized in vitro recordings from human mTLE brain tissue and in vivo recordings from a mouse epilepsy model to test antiseizure efficacy.

Main Results:

• Both PCPZ and CLP-257 enhanced KCC2 function and clustering in cortical neurons without altering phosphorylation.
• CLP-257 selectively increased extrasynaptic GABA_A receptor currents.
• PCPZ and CLP-257 (or its prodrug CLP-290) significantly suppressed spontaneous epileptiform activity in both human mTLE tissue and a mouse epilepsy model.

Conclusions:

• PCPZ and CLP-257 are confirmed KCC2 enhancers that modulate neuronal chloride homeostasis.
• These compounds demonstrate significant antiseizure effects in relevant epilepsy models.
• KCC2-enhancing compounds represent a promising therapeutic avenue for drug-resistant mTLE.