Degraded dendritic input feature detection underlies spatial memory deficits in epilepsy

Nicola Masala¹, Martin Pofahl¹, Negar Nikbakht¹, Andre Haubrich¹, Tony Kelly¹, Heinz Beck¹

¹ IEECR

Memory deficits are a debilitating symptom of epilepsies in patients. While considerable attention has been devoted to studying mechanisms of seizure generation, much less is known about mechanisms underlying cognitive deficits, and how to reverse them. We describe a Na⁺ channel dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding in-vivo, and deficits in spatial memory.

Using two-photon glutamate uncaging, we have found that the known mechanisms constraining Na⁺ channel driven spikes in 1^st order hippocampal neuron dendrites are profoundly degraded in epileptic mice. This deficit could be reversed by a selective Na_v1.3 sodium channel blocker, but not by Na⁺ channel blockers that affect other Na⁺ channel isoforms. In-vivo 2-photon imaging revealed that spatial representations in hippocampal neurons were significantly less precise in epileptic mice. Blocking Nav1.3 channels significantly improved the precision of spatial coding, and reversed hippocampal memory deficits in epileptic animals.

Thus, a dendritic channelopathy that can be pharmacologically targeted may underlie cognitive deficits in epilepsy. This mechanism of degraded cognition may constitute a new avenue to enhance cognition in chronic epilepsy.