Cargando…

Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum

Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer’s disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and corte...

Descripción completa

Detalles Bibliográficos
Autores principales: Lisgaras, Christos Panagiotis, Scharfman, Helen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10617404/
https://www.ncbi.nlm.nih.gov/pubmed/37714307
http://dx.doi.org/10.1016/j.nbd.2023.106294
_version_ 1785129600000458752
author Lisgaras, Christos Panagiotis
Scharfman, Helen E.
author_facet Lisgaras, Christos Panagiotis
Scharfman, Helen E.
author_sort Lisgaras, Christos Panagiotis
collection PubMed
description Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer’s disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.
format Online
Article
Text
id pubmed-10617404
institution National Center for Biotechnology Information
language English
publishDate 2023
record_format MEDLINE/PubMed
spelling pubmed-106174042023-10-31 Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum Lisgaras, Christos Panagiotis Scharfman, Helen E. Neurobiol Dis Article Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer’s disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD. 2023-10-15 2023-09-14 /pmc/articles/PMC10617404/ /pubmed/37714307 http://dx.doi.org/10.1016/j.nbd.2023.106294 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Lisgaras, Christos Panagiotis
Scharfman, Helen E.
Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title_full Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title_fullStr Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title_full_unstemmed Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title_short Interictal spikes in Alzheimer’s disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
title_sort interictal spikes in alzheimer’s disease: preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10617404/
https://www.ncbi.nlm.nih.gov/pubmed/37714307
http://dx.doi.org/10.1016/j.nbd.2023.106294
work_keys_str_mv AT lisgaraschristospanagiotis interictalspikesinalzheimersdiseasepreclinicalevidencefordominanceofthedentategyrusandcholinergiccontrolbythemedialseptum
AT scharfmanhelene interictalspikesinalzheimersdiseasepreclinicalevidencefordominanceofthedentategyrusandcholinergiccontrolbythemedialseptum