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bioRxiv · 10.1101/2020.11.23.393694

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

Masala, N.·Pofahl, M.·Haubrich, A. N.·Nikbakht, N.·Bohmbach, K.·Henneberger, C.·Golcuk, K.·Kelly, T.·Beck, H.
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Abstract

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. A selective Nav1.3 sodium channel blocker reversed this effect, and Nav1.3 channels were up-regulated selectively in principal neurons at the mRNA level. Finally, in-vivo two-photon imaging revealed that the Nav1.3 channel blocker improves degraded hippocampal spatial representations, and reverses 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. One Sentence SummaryImpaired input computations via aberrant dendritic spikes in chronic epilepsy degrade neuronal place codes and spatial memory

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Masala, N., Pofahl, M., Haubrich, A. N., Nikbakht, N., Bohmbach, K., Henneberger, C., Golcuk, K., Kelly, T., Beck, H.. 2020-11-23. Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy. https://doi.org/10.1101/2020.11.23.393694

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