Consequences of acute Na_v1.1 exposure to deltamethrin

Pyrethroid insecticides are the most popular class of insecticides in the world, despite their near-ubiquity, their effects of delaying the onset of inactivation of voltage-gated sodium (Na_v) channels have not been well-evaluated in all the mammalian Na_v isoforms.

Here we compare the well-studied Na_v1.6 isoforms to the less-understood Na_v1.1 in their responses to acute deltamethrin exposure.

We used patch-clamp electrophysiology to record sodium currents encoded by either Na_v1.1 or Na_v1.6 channels stably expressed in HEK293 cells. Protocols evaluating both resting and use-dependent modification were employed.

We found that exposure of both isoforms to 10μM deltamethrin significantly potentiated persistent and tail current densities without affecting peak transient current densities, and only Na_v1.1 maintained these significant effects at 1μM deltamethrin. Window currents increased for both as well, and while only Na_v1.6 displayed changes in activation slope and V_1/2 of steady-state inactivation for peak currents, V_1/2 of persistent current activation was hyperpolarized of ∼10mV by deltamethrin in Na_v1.1 cells. Evaluating use-dependence, we found that deltamethrin again potentiated persistent and tail current densities in both isoforms, but only Na_v1.6 demonstrated use-dependent enhancement, indicating the primary deltamethrin-induced effects on Na_v1.1 channels are not use-dependent.

Collectively, these data provide evidence that Na_v1.1 is indeed vulnerable to deltamethrin modification at lower concentrations than Na_v1.6, and this effect is primarily mediated during the resting state.

These findings identify Na_v1.1 as a novel target of pyrethroid exposure, which has major implications for the etiology of neuropsychiatric disorders associated with loss of Na_v1.1-expressing inhibitory neurons.