Abstract
Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and backpropagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes backpropagation of APs to the soma. Here, we show the Small Ubiquitin-like Modifier (SUMO) pathway modulates persistent sodium current (INaP) generation at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.
Significance Statement Resolving a long-standing controversy, SUMOylation of NaV1.2 channels is revealed to regulate the excitability of cortical neurons by augmenting persistent sodium current at critical subthreshold voltages. SUMOylation increases the speed of action potential backpropagation from the axon initial segment to the soma, a phenomenon critical to long-term potentiation, spike-time dependent plasticity, and release of retrograde factors essential to synaptic plasticity and development.
Competing Interest Statement
The authors have declared no competing interest.
