SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons.

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 propagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the small ubiquitin-like modifier (SUMO) pathway modulates Na+ channels 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.

Temperature-robust rapid eye movement and slow wave sleep in the lizard Laudakia vulgaris.

During sleep our brain switches between two starkly different brain states - slow wave sleep (SWS) and rapid eye movement (REM) sleep. While this two-state sleep pattern is abundant across birds and mammals, its existence in other vertebrates is not universally accepted, its evolutionary emergence is unclear and it is undetermined whether it is a fundamental property of vertebrate brains or an adaptation specific to homeotherms. To address these questions, we conducted electrophysiological recordings in the Agamid lizard, Laudakia vulgaris during sleep. We found clear signatures of two-state sleep that resemble the mammalian and avian sleep patterns. These states switched periodically throughout the night with a cycle of ~90 seconds and were remarkably similar to the states previously reported in Pogona vitticeps. Interestingly, in contrast to the high temperature sensitivity of mammalian states, state switches were robust to large variations in temperature. We also found that breathing rate, micro-movements and eye movements were locked to the REM state as they are in mammals. Collectively, these findings suggest that two-state sleep is abundant across the agamid family, shares physiological similarity to mammalian sleep, and can be maintain in poikilothems, increasing the probability that it existed in the cold-blooded ancestor of amniotes.

Subcellular distribution of persistent sodium conductance in cortical pyramidal neurons.

Cortical pyramidal neurons possess a persistent Na+ current (INaP) which, in contrast to the larger transient current, does not undergo rapid inactivation. Although relatively quite small, INaP is active at subthreshold voltages and therefore plays an important role in neuronal input-output processing. The subcellular distribution of channels responsible for INaP and the mechanisms which render them persistent are not known. Using high-speed fluorescence Na+ imaging and whole-cell recordings in brain slices obtained from mice of either sex, we reconstructed the INaP elicited by slow voltage ramps in soma and processes of cortical pyramidal neurons. We found that in all neuronal compartments, the relationship between persistent Na+ conductance and membrane voltage has the shape of a Boltzmann function. Although the density of channels underlying INaP was about twofold lower in the axon initial segment (AIS) than in the soma, the axonal channels were activated by about 10 mV less depolarization than were somatic channels. This difference in voltage dependence explains why, at functionally critical subthreshold voltages, most INaP originates in the AIS. Finally, we show that endogenous polyamines constrain INaP availability in both somato-dendritic and axonal compartments of non-dialyzed cortical neurons.SIGNIFICANCE STATEMENT:The most salient characteristic of neuronal sodium channels is fast inactivation. However, a fraction of the sodium current does not inactivate. In cortical neurons, persistent current (INaP) plays a prominent role in many important functions. Its subcellular distribution and generation mechanisms are, however, elusive. Using high-speed fluorescence Na+ imaging and electrical recordings, we reconstructed the INaP in soma and processes of cortical pyramidal neurons. We found that at near-threshold voltages INaP originates predominately from the axon, due to the distinctive voltage dependence of the underlying channels and not because of their high density. Finally, we show that the presence of endogenous polyamines significantly constrains INaP availability in all compartments of non-dialyzed cortical neurons.