The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons.

Xincai Ji,Gilles E Martin,Melissa Guildford,Guangping Gao,Gregg E Homanics,Sucharita Saha,Andrew R Tapper,Amy W Lasek

doi:10.3389/fncel.2017.00017

Abstract

Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1–4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens – NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered the properties of APs in core accumbens medium spiny neurons (MSNs). These alterations are associated with a reduction of the probability of MSNs to evoke spike-timing-dependent long-term depression (tLTD) and a reduced ability of backpropagating APs to evoke dendritic calcium transients. In contrast, long-term potentiation (tLTP) remained unaffected. Interestingly, we also showed that amphetamine-induced locomotor activity was significantly reduced in male Scn4b KO mice compared to wild-type controls. Taken together, these data indicate that the Scn4b subunit selectively controls tLTD by modulating dendritic calcium transients evoked by backpropagating APs.

Highlights

It has long been established that adaptation of organisms to their environment depends in part on neuron-to-neuron propagation of action potentials (APs) throughout the brain
We provide for the first time, evidence indicating that low or no Scn4b expression dramatically impairs the ability of NAc medium spiny neurons (MSNs) to evoke timing-dependent long-term depression (tLTD), a consequence of attenuated dendritic calcium transients
The ability of APs to drive calcium transients in dendrites is attenuated in KO mice, an effect mostly observed in secondary dendrites

Summary

Introduction

It has long been established that adaptation of organisms to their environment depends in part on neuron-to-neuron propagation of action potentials (APs) throughout the brain. Given the wellestablished role of the accumbens in mediating amphetamineinduced locomotor activity (Kelly et al, 1975; Pijnenburg et al, 1976), we tested whether alteration of the balance between tLTP and tLTD in mice lacking the Scn4b subunit impacted the effects of amphetamine on this behavior. Taken together, these data suggest that the Scn4b subunit selectively controls tLTD formation by attenuating dendritic calcium transients following alteration of APs, effect that may be necessary for the psychostimulant action of amphetamine

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Conclusion