Pathogenic gating pore current conducted by autism-related mutations in the Na V 1.2 brain sodium channel.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ /K _V 7 potassium channel cause gating pore currents (I _gp ) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A /Na _V 1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na _V 1.2 caused I _gp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I _gp . These potentially pathogenic I _gp were exacerbated by the absence of the extracellular Mg ²⁺ and Ca ²⁺ . In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I _gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.
Competing Interests: Competing interests statement:B.N.L. has no personal financial interests and declares intellectual property licensed to Cadence Neuroscience Inc (contractual rights waived; all funds to Mayo Clinic) and Seer Medical Inc (contractual rights waived; all funds to Mayo Clinic), site investigator (Medtronic EPAS, Neuroelectrics tDCS for Epilepsy), and industry consultant (Epiminder, Medtronic, Neuropace, Philips Neuro; all funds to Mayo Clinic). Other authors have no financial interests. T.Z., Chahine, and T.M.G.E.-D. were guest editors for a special issue entitled “Druggability of voltage-gated sodium and calcium channels” in 2022. As a part of their job as guest editors, they wrote an editorial article to highlight the main features of the published papers in this special issue.