Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

• DOI: 10.1093/brain/awac455
• Publication Date: 2022-11-30T14:54:15Z
• Authors: Nicola Masala; Martin Pofahl; André N Haubrich; Khondker Ushna Sa...; Negar Nikbakht; Maryam Pasdarnavab; Kirsten Bohmbach; Kunihiko Araki; Fateme Kamali; Christian Hennebe...; Kurtulus Golcuk; Laura A Ewell; Sandra Blaess; Tony Kelly; Heinz Beck
• Keywords: Biomedical and clinical sciences; dendritic spike; Biological Psychology; physiology [Hippocampus]; Action Potentials; Neurodegenerative; Basic Behavioral and Social Science; Medical and Health Sciences; Hippocampus; Mice; Behavioral and Social Science; physiology [Action Potentials]; Acetamides; Psychology; 2.1 Biological and endogenous factors; Animals; ddc:610; Aetiology; cognitive comorbidities; Neurology & Neurosurgery; Epilepsy; Biomedical and Clinical Sciences; Pyramidal Cells; Psychology and Cognitive Sciences; Neurosciences; Health sciences; Pharmacology and Pharmaceutical Sciences; physiology [Dendrites]; Dendrites; Brain Disorders; dendritic integration; metabolism [Pyramidal Cells]; calcium imaging; metabolism [Acetamides]; Neurological; epilepsy; Original Article; metabolism [Epilepsy]; ICA-121431

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.