TY  - JOUR
AU  - Masala, Nicola
AU  - Pofahl, Martin
AU  - Haubrich, André N
AU  - Sameen Islam, Khondker Ushna
AU  - Nikbakht, Negar
AU  - Pasdarnavab, Maryam
AU  - Bohmbach, Kirsten
AU  - Araki, Kunihiko
AU  - Kamali, Fateme
AU  - Henneberger, Christian
AU  - Golcuk, Kurtulus
AU  - Ewell, Laura A
AU  - Blaess, Sandra
AU  - Kelly, Tony
AU  - Beck, Heinz
TI  - Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.
JO  - Brain
VL  - 146
IS  - 6
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2023-00587
SP  - 2399 - 2417
PY  - 2023
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Dendrites: physiology
KW  - Hippocampus: physiology
KW  - Acetamides: metabolism
KW  - Pyramidal Cells: metabolism
KW  - Epilepsy: metabolism
KW  - Action Potentials: physiology
KW  - calcium imaging (Other)
KW  - cognitive comorbidities (Other)
KW  - dendritic integration (Other)
KW  - dendritic spike (Other)
KW  - epilepsy (Other)
KW  - ICA-121431 (NLM Chemicals)
KW  - Acetamides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36448426
C2  - pmc:PMC10232249
DO  - DOI:10.1093/brain/awac455
UR  - https://pub.dzne.de/record/258241
ER  -