Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

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 glut...

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Published inbioRxiv
Main Authors Masala, Nicola, Pofahl, Martin, Haubrich, Andre Nathan, Khondker Ushna Sameen Islam, Nikbakht, Negar, Pasdarnavab, Maryam, Kamali, Fateme, Bohmbach, Kirsten, Henneberger, Christian, Kurtulus Golcuk, Ewell, Laura A, Blaess, Sandra, Kelly, Tony, Beck, Heinz
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.10.2021
Subjects
Animal memory
Channelopathy
Cognitive ability
Dendrites
Epilepsy
Hippocampus
Integration
Memory
Sodium channels (voltage-gated)
Spatial discrimination
Spatial memory
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Summary: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. Competing Interest Statement The authors have declared no competing interest. Footnotes * Author affiliations updated Supplemental files updated
DOI:10.1101/2020.11.23.393694