Scn2a, encoding NaV1.2 channel, contributes to tonotopic maturation of spike kinetics in developing mouse MNTB

Introduction SCN2A , encoding the voltage-gated sodium channel Na V 1.2, is a high-risk gene associated with autism spectrum disorder (ASD) and has been linked to sensory hypersensitivity. Recent work indicates that Na V 1.2 loss-of-function produces developmental and compartment specific alterations in neuronal signaling. However, how SCN2A contributes to the maturation of subcortical auditory circuits that demand exceptional temporal precision remains unclear. Methods In this study, using Scn2a haploinsufficient ( Scn2a +/– ) mice, we investigated the functional contribution of Na V 1.2 to spike-generating mechanisms in the medial nucleus of the trapezoid body (MNTB), a fast inhibitory relay in the auditory brainstem organized along a medial–lateral tonotopic axis. Results In the pre-hearing period (P4–P6), Scn2a haploinsufficiency reduced transient Na + current amplitude and eliminated a delayed onset inward Na + current component observed in a subset of wild type neurons, providing functional evidence for Na V 1.2 dependent activity in developing MNTB neurons. Notably, Na V 1.2 dependent deficits were tonotopically patterned. Lateral (low frequency) MNTB neurons exhibited the largest reductions in both transient Na + current and persistent Na + current, whereas medial neurons were comparatively spared in peak current magnitude. In current clamp, Scn2a +/– neurons displayed altered action potential kinetics during the pre-hearing window (slower and broader spikes), but repetitive firing during prolonged depolarizing steps was largely preserved, indicating that Scn2a reduction impacts spike waveform maturation more than tonic spike count. After hearing onset, peak Na + current amplitudes were comparable between genotypes (P14-P24), consistent with developmental reorganization of Na V channel contributions. Discussion Together, these findings identify a pre-hearing, tonotopically biased role for Scn2a in axon initial segment (AIS)-linked Na + channel function and spike kinetics in the MNTB, providing a mechanistic framework for how Scn2a may influence early auditory brainstem development relevant to sensory phenotypes in ASD.