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; ... (2023). Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease. Nature neuroscience, 26(6), pp. 1021-1031. Nature America 10.1038/s41593-023-01325-4
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Sahli Building > Forschungsgruppe Neurologie |
UniBE Contributor: |
Bozic, Ivan, Rusterholz, Thomas, Adamantidis, Antoine Roger |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1097-6256 |
Publisher: |
Nature America |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
16 May 2023 09:59 |
Last Modified: |
08 Jun 2023 00:15 |
Publisher DOI: |
10.1038/s41593-023-01325-4 |
PubMed ID: |
37188873 |
BORIS DOI: |
10.48350/182608 |
URI: |
https://boris.unibe.ch/id/eprint/182608 |
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