Abstract
(from Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease, from Calafate et al, 2023)
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.
Method
Immunohistochemistry, imaging and quantification
Mice were anesthetized with ketamine (0.2 mg per gram body weight) and xylazine (0.02 mg per gram body weight) intraperitoneally administered, perfused with 1× PBS for 1 min followed by 10 min of 4% paraformaldehyde (PFA) in PBS. Brains were post-fixed for 4 h in 4% PFA, washed in 1× PBS and embedded in 3% agarose. Then, 50-µm sections were prepared using a vibratome (Campden Instruments 7000smz). Sections were permeabilized with 0.5% Triton in PBS-0.2% gelatin for 30 min, blocked for 2 h in 10% normal horse serum and 0.5% Triton in PBS-0.2% gelatin. Primary antibodies were incubated for 48 h and secondary antibodies for 24 h. Primary and secondary antibodies were diluted in 5% normal horse serum and 0.5% triton in PBS-0.2% gelatin. Hoechst was used as a nuclear stain (5 nM in PBS).
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