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MELANIN CONCENTRATING HORMONE- AND SLEEP-DEPENDENT SYNAPTIC DOWNSCALING IS IMPAIRED IN ALZHEIMER’S DISEASE
Abstract
Aims
In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Neuronal hyperactivity and increased risk for seizure is observed early in AD, and occurs many years before cognitive decline onset. This period is characterized by a complex interplay of molecular events that lead to cellular alterations in all brain cell types, and over many years, result in chronic inflammation, neuronal death and cognitive impairment
Methods
Using electrophysiology recordings and neuronal activity monitoring we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene.
Results
MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients.
Conclusions
Our work identifies the MCH-system as a key player maintaining synapse homeostasis in early stages of AD. Dysregulation of this system can underlie aberrant neuronal activity and modulate the risk for seizure through different molecular candidates in the early stages of AD.