文章基本信息

标题：Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease
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作者：Chommanad Lerdkrai ; Nithi Asavapanumas ; Bianca Brawek 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：6
页码：E1279-E1288
DOI：10.1073/pnas.1714409115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Neuronal hyperactivity is the emerging functional hallmark of Alzheimer’s disease (AD) in both humans and different mouse models, mediating an impairment of memory and cognition. The mechanisms underlying neuronal hyperactivity remain, however, elusive. In vivo Ca²⁺ imaging of somatic, dendritic, and axonal activity patterns of cortical neurons revealed that both healthy aging and AD-related mutations augment neuronal hyperactivity. The AD-related enhancement occurred even without amyloid deposition and neuroinflammation, mainly due to presenilin-mediated dysfunction of intracellular Ca²⁺ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors. In mutant but not wild-type mice, store emptying reduced both the frequency and amplitude of presynaptic Ca²⁺ transients and, most importantly, normalized neuronal network activity. Postsynaptically, the store dysfunction was minor and largely restricted to hyperactive cells. These findings identify presynaptic Ca²⁺ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments.
关键词：amyloidosis ; synaptic impairment ; axonal boutons ; dendritic calcium stores ; NMDA