Transcriptional control of NaV channel expression fine-tunes neuronal excitability during AIS long-term plasticity

Activity level in neuronal networks is dynamically regulated to prevent network hyper- or hypo-activity. Homeostatic plasticity mechanisms allow the fine-tuning of synaptic strength and intrinsic excitability. Crucial compartment for excitability regulation is the axon initial segment (AIS), as changes in AIS structure, but also voltage-gated ion channel type and density are known to occur during changes in activity and strongly influence action potential firing properties. However, the molecular mechanisms controlling AIS plasticity, and thereby allowing the AIS to dynamically regulate intrinsic excitability are still elusive. 
Here, we show that the AIS scaffold AnkyrinG does not undergo strucural plasticity in cultured hippocampal neurons following 48 hours of network silencing. However, Patch-clamp recordings reveal that glutamatergic neurons exhibited a significant increase in their intrinsic excitability, contrary to GABAergic neurons. Using immunocytochemistry, we report that chronic silencing triggers an increase in 
Sodium channel NaV1.6 density at the AIS in excitatory neurons, and a decrease in inhibitory neurons. Furthermore, we find that that protein synthesis is needed for the upregulation of NaV1.6 channels in excitatory neurons, associated with an increase in SCN8A transcripts, encoding NaV1.6. We also report a specific upregulation of Rbfox1, a transcription factor known to activate SCN8A trasncription, in glutamatergic cells. Altogether, we reveal how NaV1.6 expression is regulated by changes in activity, allowing neurons to modulate their intrinsic excitability, thereby counterbalancing the alterations of network activity.
 

Amélie Fréal est invitée par Leticia Peris.