Jinjing Yao1,2, Yajing Liu1,3, Bo Sun1,4, Xiaoqin Zhan5, John Paul Estillore1, Ray W Turner5, S R Wayne Chen1,2. 1. Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 2. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 3. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China. 4. Medical School, Kunming University of Science and Technology, Kunming, China. 5. Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Abstract
INTRODUCTION: Neuronal hyperactivity is an early neuronal defect commonly observed in familial and sporadic Alzheimer's disease (AD), but the underlying mechanisms are unclear. METHODS: We employed a ryanodine receptor 2 (RyR2) mutant mouse model harboring the R4496C+/- mutation that markedly increases the channel's open probability (Po) to determine the impact of increased RyR2 activity in neuronal function without AD gene mutations. RESULTS: Genetically increasing RyR2 Po induced neuronal hyperactivity in vivo in anesthetized and awake mice. Increased RyR2 Po induced hyperactive behaviors, impaired learning and memory, defective dendritic spines, and neuronal cell death. Increased RyR2 Po exacerbated the onset of neuronal hyperexcitability and learning and memory impairments in 5xFAD mice. DISCUSSION: Increased RyR2 Po exacerbates the onset of familial AD-associated neuronal dysfunction, and induces AD-like defects in the absence of AD-causing gene mutations, suggesting that RyR2-associated neuronal hyperactivity represents a common target for combating AD with or without AD gene mutations.
INTRODUCTION: Neuronal hyperactivity is an early neuronal defect commonly observed in familial and sporadic Alzheimer's disease (AD), but the underlying mechanisms are unclear. METHODS: We employed a ryanodine receptor 2 (RyR2) mutant mouse model harboring the R4496C+/- mutation that markedly increases the channel's open probability (Po) to determine the impact of increased RyR2 activity in neuronal function without AD gene mutations. RESULTS: Genetically increasing RyR2 Po induced neuronal hyperactivity in vivo in anesthetized and awake mice. Increased RyR2 Po induced hyperactive behaviors, impaired learning and memory, defective dendritic spines, and neuronal cell death. Increased RyR2 Po exacerbated the onset of neuronal hyperexcitability and learning and memory impairments in 5xFAD mice. DISCUSSION: Increased RyR2 Po exacerbates the onset of familial AD-associated neuronal dysfunction, and induces AD-like defects in the absence of AD-causing gene mutations, suggesting that RyR2-associated neuronal hyperactivity represents a common target for combating AD with or without AD gene mutations.
Authors: Ruei-Lung Lin; Hilaree N Frazier; Katie L Anderson; Sami L Case; Adam O Ghoweri; Olivier Thibault Journal: Aging Cell Date: 2022-06-19 Impact factor: 11.005
Authors: Shane M Ohline; Xinhuai Liu; Mohamed F Ibrahim; Bruce M Mockett; Ruth M Empson; Wickliffe C Abraham; Karl J Iremonger; Peter P Jones Journal: Front Cell Neurosci Date: 2022-08-26 Impact factor: 6.147