Sodium channel endocytosis drives axon initial segment plasticity

Abstract

Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action potential initiation at the AIS highly depends on the clustering of voltage-gated sodium channels, however the molecular mechanisms regulating their plasticity remain largely unknown. Here, we used novel genetic tools to endogenously label sodium channels and their scaffolding protein, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons, in slices and primary cultures. We find that induction of NMDA receptor-mediated long-term synaptic depression is linked to a rapid and local endocytosis of sodium channels from the distal AIS. These data reveal a novel fundamental mechanism for rapid activity-dependent AIS reorganization sharing conserved features with synaptic plasticity.

Structural plasticity of the axon initial segment in rat hippocampal granule cells following high frequency stimulation and LTP induction

“…Strikingly, not only non-physiological conditions such as high extracellular potassium (Grubb and Burrone, 2010;Evans et al, 2015), but also network stimulations in a physiological context, resulted in rapid AIS shortening (Jamann et al, 2021). Likewise, a recent study reported an NMDA-receptor-dependent reduction in AIS length within half an hour after induction of chemical long-term depression (Fréal et al, 2022).…”