Sodium channel subtypes are differentially localized to pre- and post-synaptic sites in rat hippocampus

Voltage-gated Na⁺ channels (Na_v ) modulate neuronal excitability, but the roles of the various Na_v subtypes in specific neuronal functions such as synaptic transmission are unclear. We investigated expression of the three major brain Na_v subtypes (Na_v 1.1, Na_v 1.2, Na_v 1.6) in area CA1 and dentate gyrus of rat hippocampus. Using light and electron microscopy, we found labeling for all three Na_v subtypes on dendrites, dendritic spines, and axon terminals, but the proportion of pre- and post-synaptic labeling for each subtype varied within and between subregions of CA1 and dentate gyrus. In the central hilus (CH) of the dentate gyrus, Na_v 1.1 immunoreactivity was selectively expressed in presynaptic profiles, while Na_v 1.2 and Na_v 1.6 were expressed both pre- and post-synaptically. In contrast, in the stratum radiatum (SR) of CA1, Na_v 1.1, Na_v 1.2, and Na_v 1.6 were selectively expressed in postsynaptic profiles. We next compared differences in Na_v subtype expression between CH and SR axon terminals and between CH and SR dendrites and spines. Na_v 1.1 and Na_v 1.2 immunoreactivity was preferentially localized to CH axon terminals compared to SR, and in SR dendrites and spines compared to CH. No differences in Na_v 1.6 immunoreactivity were found between axon terminals of CH and SR or between dendrites and spines of CH and SR. All Na_v subtypes in both CH and SR were preferentially associated with asymmetric synapses rather than symmetric synapses. These findings indicate selective presynaptic and postsynaptic Na_v expression in glutamatergic synapses of CH and SR supporting neurotransmitter release and synaptic plasticity.