Objective:Loss-of-function mutations in NIPA2 are associated with childhood absence epilepsy (CAE). The aim of this study is to investigate how the absence of NIPA2 affects neural excitability.

Methods:We performed whole-cell patch-clamp recordings to measure electrophysiological properties of neocortical somatosensory pyramidal neurons in wild-type (WT) and the NIPA2 knockout mice. These electrophysiological properties included spontaneous and evoked action potential (AP) and the currents of big-conductance potassium channels (BK channels).

Results:We have identified that neocortical somatosensory pyramidal neurons isolated from 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. Specific BK channel opener, NS11021, reduced neuronal excitability in the NIPA2 knockout mice. Furthermore, paxilline, a selective BK channel blocker, treated WT neurons, and it could simulate the situation of NIPA2 knockout group. They suggested that the absence of NIPA2 enhanced excitability of neocortical somatosensory pyramidal neurons by decreasing the currents of BK channels.

Significance:We confirm that NIPA2 is probably a susceptibility gene of epilepsy, and mutated NIPA2 enhanced neural excitability through BK channels. This provides an important clue to develop new treatment strategy for epilepsy.