Nature neuroscience · 2023
Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Calafate Sara, Özturan Gökhan, Thrupp Nicola, Vanderlinden Jeroen, Santa-Marinha Luísa, Morais-Ribeiro Rafaela, Ruggiero Antonella, Bozic Ivan, Rusterholz Thomas, Lorente-Echeverría Blanca, Dias Marcelo, Chen Wei-Ting, Fiers Mark, Lu Ashley, Vlaeminck Ine, Creemers Eline, Craessaerts Katleen, Vandenbempt Joris, van Boekholdt Luuk, Poovathingal Suresh, Davie Kristofer, Thal Dietmar Rudolf, Wierda Keimpe, Oliveira Tiago Gil, Slutsky Inna, Adamantidis Antoine, De Strooper Bart, de Wit Joris
Аннотация
Early Alzheimer's disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.