TY - JOUR
T1 - Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease
AU - Calafate, Sara
AU - Özturan, Gökhan
AU - Thrupp, Nicola
AU - Vanderlinden, Jeroen
AU - Santa-Marinha, Luísa
AU - Morais-Ribeiro, Rafaela
AU - Ruggiero, Antonella
AU - Bozic, Ivan
AU - Rusterholz, Thomas
AU - Lorente-Echeverría, Blanca
AU - Dias, Marcelo
AU - Chen, Wei Ting
AU - Fiers, Mark
AU - Lu, Ashley
AU - Vlaeminck, Ine
AU - Creemers, Eline
AU - Craessaerts, Katleen
AU - Vandenbempt, Joris
AU - van Boekholdt, Luuk
AU - Poovathingal, Suresh
AU - Davie, Kristofer
AU - Thal, Dietmar Rudolf
AU - Wierda, Keimpe
AU - Oliveira, Tiago Gil
AU - Slutsky, Inna
AU - Adamantidis, Antoine
AU - De Strooper, Bart
AU - de Wit, Joris
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - 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 App NL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in App NL-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 App NL-G-F mice. App NL-G-F mice spend less time in rapid eye movement (REM) sleep. App NL-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.
AB - 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 App NL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in App NL-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 App NL-G-F mice. App NL-G-F mice spend less time in rapid eye movement (REM) sleep. App NL-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.
UR - http://www.scopus.com/inward/record.url?scp=85159273259&partnerID=8YFLogxK
U2 - 10.1038/s41593-023-01325-4
DO - 10.1038/s41593-023-01325-4
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C2 - 37188873
AN - SCOPUS:85159273259
SN - 1097-6256
VL - 26
SP - 1021
EP - 1031
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 6
ER -