Sodium channel β2 subunits prevent action potential propagation failures at axonal branch points

Abstract

Neurotransmitter release depends on voltage-gated Na+channels (Navs) to propagate an action potential (AP) successfully from the axon hillock to a synaptic terminal. Unmyelinated sections of axon are very diverse structures encompassing branch points and numerous presynaptic terminals with undefined molecular partners of Na+channels. Using optical recordings of Ca2+and membrane voltage, we demonstrate here that Na+channelβ2 subunits (Navβ2s) are required to prevent AP propagation failures across the axonal arborization of cultured rat hippocampal neurons (mixed male and female). When Navβ2 expression was reduced, we identified two specific phenotypes: (1) membrane excitability and AP-evoked Ca2+entry were impaired at synapses and (2) AP propagation was severely compromised with> 40% of axonal branches no longer responding to AP-stimulation. We went on to show that a great deal of electrical signaling heterogeneity exists in AP waveforms across the axonal arborization independent of axon morphology. Therefore, Navβ2 is a critical regulator of axonal excitability and synaptic function in unmyelinated axons.