The absence of NIPA2 enhances neural excitability through BK (big potassium) channels.

Aim: To reveal the pathogenesis and find the precision treatment for the childhood absence epilepsy (CAE) patients with NIPA2 mutations.

Methods: We performed whole-cell patch-clamp recordings to measure the electrophysiological properties of layer V neocortical somatosensory pyramidal neurons in wild-type (WT) and NIPA2-knockout mice.

Results: We identified that layer V neocortical somatosensory pyramidal neurons isolated from the NIPA2-knockout mice displayed higher frequency of spontaneous and evoked action potential, broader half-width of evoked action potential, and smaller currents of BK channels than those from the WT mice. NS11021, a specific BK channel opener, reduced neuronal excitability in the NIPA2-knockout mice. Paxilline, a selective BK channel blocker, treated WT neurons and could simulate the situation of NIPA2-knockout group, thereby suggesting that the absence of NIPA2 enhanced the excitability of neocortical somatosensory pyramidal neurons by decreasing the currents of BK channels. Zonisamide, an anti-epilepsy drug, reduced action potential firing in NIPA2-knockout mice through increasing BK channel currents.

Conclusion: The results indicate that the absence of NIPA2 enhances neural excitability through BK channels. Zonisamide is probably a potential treatment for NIPA2 mutation-induced epilepsy, which may provide a basis for the development of new treatment strategies for epilepsy.