In a study published in the scientific journal eLife, neuroscientists at the University of California have used a novel method to reveal the unique roles of specific forms of voltage-gated ion channels in regulating neuron excitability. The findings open for new ways to treat neurological conditions such as epilepsy, using selective control of neuron excitability.
The researchers, led by Dr. Kevin J. Bender, used a group of compounds called aryl sulfonamides (ASCs) to selectively block voltage-gated sodium channels of the subtypes NaV1.2 and NaV1.6. These channels are essential for initiating and propagating electrical signals in the brain.
Voltage-gated sodium channels are not one-size-fits-all. Each subtype has a distinct localization in neurons and plays a different role. NaV1.6, for example, dominates the distal axon initial segment (AIS) and is central to action potential initiation, while NaV1.2 is primarily found in dendrites and the proximal AIS, influencing backpropagation and signal integration.
To dissect the roles of these isoforms with unprecedented precision, the researchers genetically engineered mice to alter just two amino acids in the sodium channels. This change allowed the team to use the ASC compound GNE-4076 to acutely and selectively inhibit either NaV1.2 or NaV1.6 in otherwise normal neurons, without inducing long-term compensatory changes typically seen in genetic knockouts.
When blocking NaV1.2, the researchers showed that ion channel inhibition resulted in increased pyramidal neuron excitability. This result likely stems from the decreased potassium channel recruitment due to reduced dendrite depolarization, facilitating faster re-firing of neurons. In contrast, inhibiting NaV1.6 led to increased spike thresholds and reduced firing, confirming its pivotal role in initiating neural activity.
The researchers further demonstrated that GNE-4076 works in a use-dependent manner for normal spiking neurons experiencing physiological levels of activity, meaning its inhibitory effects increase with neural activity. This constitutes a valuable property for potential therapeutic applications targeting overactive neural circuits in conditions like epilepsy.
In their study, the researchers used Fluicell’s Dynaflow Resolve system to investigate the effect of varying concentrations of GNE-4076 on ion channel activation and inactivation in cells, expressing both wild type or mutant forms of NaV1.2 and NaV1.6. This allowed the team to perform detailed dose-response experiments and tightly control drug application timing, demonstrating the ability to specifically target individual isoforms.
The results presented by Dr. Bender and colleagues demonstrate that blocking of NaV1.2 and NaV1.6 have distinct and opposite effects on neuron excitability and constitutes a new way of thinking about ion channel targeting pharmaceuticals. Instead of silencing all neuronal activity, compounds such as ASC that enable activity-dependent inactivation of NaV1.6 provide a path forward for finding new ways to treat epilepsy and other neurological conditions.
We congratulate Dr. Bender and colleagues on their achievements and are grateful that they have chosen to use Dynaflow Resolve in their important research.
- Read the article Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability on the eLife website.