Activity-dependent formation and location of voltage-gated sodium channel clusters at a CNS nerve terminal during...

In auditory pathways, the precision of action potential (AP) propagation depends on axon myelination and high densities of voltage-gated Na (Na_v) channels clustered at nodes of Ranvier. Changes in Na_v channel expression at the heminode, the final node before the nerve terminal, can alter AP invasion into the presynaptic terminal. We studied the activity-dependent formation of Na_v channel clusters before and after hearing onset at postnatal day 12 in the rat and mouse auditory brain stem. In rats, the Na_v channel cluster at the heminode formed progressively during the second postnatal week, around hearing onset, whereas the Na_v channel cluster at the nodes was present before hearing onset. Initiation of heminodal Na_v channel clustering was correlated with the expression of scaffolding protein ankyrinG and paranodal protein Caspr. However, in whirler mice with congenital deafness, heminodal Na_v channels did not form clusters and maintained broad expression, but Na_v channel clustering was normal at the nodes. In addition, a clear difference in the distance from the heminodal Na_v channel to the calyx across the mediolateral axis of the medial nucleus of the trapezoid body (MNTB) developed after hearing onset. In the medial MNTB, where neurons respond best to high-frequency sounds, the heminodal Na_v channel cluster was located closer to the terminal than in the lateral MNTB, where neurons respond best to low-frequency sounds. Thus sound-mediated neuronal activities are potentially associated with the refinement of the heminode adjacent to the presynaptic terminal in the auditory brain stem.

Clustering of voltage-gated sodium (Na_v) channels and their distribution along the axon, specifically at the unmyelinated axon segment next to the nerve terminal, are essential for tuning propagated action potentials. Na_v channel clusters near the nerve terminal and their location as a function of neuronal position along the mediolateral axis are controlled by auditory inputs after hearing onset. Thus sound-mediated neuronal activity influences the tonotopic organization of Na_v channels at the nerve terminal in the auditory brain stem.