Figure 6.
NaV1.6- and NaV1.6 and 1.2-targeting compounds selectively suppress action potentials in cortical excitatory pyramidal cells. Representative voltage traces from current clamp recordings of cortical neurons (A–C) and fast spiking interneurons (E, F) from selected depolarizing current injections before and after 10 min of incubation with the stated concentration of compounds. Middle panels show input–output plots of the number of APs fired normalized to the maximum number of APs of the vehicle control in the same cell against depolarizing current injection magnitude. Right panels show plots of the absolute maximum number of APs from the range of current injections in vehicle or compound. (A) XPC-7224 at 500 nM significantly inhibited AP firing from pyramidal cells (n = 3) but not fast spiking interneurons (n = 3) (D). (B) XPC-5462 at 150 nM significantly inhibited AP firing from pyramidal cells (n = 4) but not fast spiking interneurons (n = 3–4) (E). (C) CBZ at 100 μM significantly inhibited AP firing from pyramidal cells (n = 4–6) and fast spiking interneurons (n = 3) (B). Statistical significance between vehicle and compound number of APs at each current injection was tested using a two-way ANOVA followed by Bonferroni multiple comparisons test (*P <0.05). Student’s two-way paired t tests were used to test the significance of the maximal number of APs fired by each cell in vehicle or compound (*P <0.05, **P <0.01).