Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.

Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding, and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed that the mechanisms constraining the generation of Na+ spikes in hippocampal 1st order pyramidal cell dendrites are profoundly degraded in experimental epilepsy. This phenomenon was reversed by selectively blocking Nav1.3 sodium channels. In-vivo two-photon imaging revealed that hippocampal spatial representations were less precise in epileptic mice. Blocking Nav1.3 channels significantly improved the precision of spatial coding, and reversed hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.