Journal Article

DZNE-2023-00587

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.

Masala, N. ; Pofahl, M. ; Haubrich, A. N. ; Sameen Islam, K. U. ; Nikbakht, N. ; Pasdarnavab, M. ; Bohmbach, K. ; Araki, K. ; Kamali, F. ; Henneberger, C.DZNE* ; Golcuk, K. ; Ewell, L. A. ; Blaess, S. ; Kelly, T. ; Beck, H. (Last author)DZNE*

2023
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awac455

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 a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Dendrites: physiology (MeSH) ; Hippocampus: physiology (MeSH) ; Acetamides: metabolism (MeSH) ; Pyramidal Cells: metabolism (MeSH) ; Epilepsy: metabolism (MeSH) ; Action Potentials: physiology (MeSH) ; calcium imaging ; cognitive comorbidities ; dendritic integration ; dendritic spike ; epilepsy ; ICA-121431 ; Acetamides

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Contributing Institute(s):

1. Synaptic and Glial Plasticity (AG Henneberger)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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