Genetically and pharmacologically limiting RyR2 open time prevents neuronal hyperactivity of hippocampal CA1 neurons in brain slices of 5xFAD mice. (27th July 2021)

• Record Type: Journal Article
• Authors: Sun, Bo; Yao, Jinjing; Chen, Alexander W.; Estillore, John Paul; Wang, Ruiwu; Back, Thomas G.; Chen, S.R. Wayne
• Is Part Of: Neuroscience letters. Volume 758(2021)
• Publication Date: 2021-07-27
• Subjects: Alzheimer's disease -- Neuronal hyperactivity -- Ryanodine receptor 2 -- Ca2+ imaging -- Brain slices; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2021.136011
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: The N-methyl-d-glucamine (NMDG) slicing method better preserves neuronal activity. Limiting RyR2 open time prevented neuronal hyperactivity of CA1 neurons in slices. R-carvedilol prevented and rescued neuronal hyperactivity of CA1 neurons in slices. Abstract: Neuronal hyperactivity is an early, common manifestation of Alzheimer's disease (AD), and is believed to drive AD progression. Neuronal hyperactivity in the form of baseline activity (or spontaneous Ca 2+ transients) has consistently been demonstrated in mouse models of AD using two-photon in vivo Ca 2+ imaging of cortical or hippocampal neurons in anesthetized animals. Notably, these AD-related spontaneous Ca 2+ transients were hardly detected in acute hippocampal slices, probably due to neuronal damage during brain slicing. To better preserve neuronal activity, we employed the N-methyl-D-glucamine (NMDG) protective brain slicing protocol. We performed confocal in vitro Ca 2+ imaging of hippocampal CA1 neurons in optimized hippocampal slices. Consistent with previous in vivo studies, our in vitro studies using optimized brain slices also showed that limiting the open duration of the ryanodine receptor 2 (RyR2) by the RyR2 mutation E4872Q or by the R-carvedilol enantiomer prevented and rescued neuronal hyperactivity of hippocampal CA1 neurons from 5xFAD mice. Thus, genetically and pharmacologically limiting RyR2 open time prevented and rescued AD-related neuronal hyperactivity in vitro in optimized brain slices in the absence of anesthetics' influence. Our data also suggest that the NMDG protective brain slicing preparation offers an alternative means to study neuronal hyperactivity of various cell types in different brain regions, especially in regions that are not readily accessible to two-photon in vivo Ca 2+ imaging.