학술논문
Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease
Document Type
Article
Author
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
Source
Nature Neuroscience; 20230101, Issue: Preprints p1-11, 11p
Subject
Language
ISSN
10976256; 15461726
Abstract
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-Fmice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmchas part of the adaptive response in AppNL-G-Fmice. Pmchencodes 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-Fmice. AppNL-G-Fmice spend less time in rapid eye movement (REM) sleep. AppNL-G-Fmice 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.