Stimulation of the Hippocampal POMC/MC4R Circuit Alleviates Synaptic Plasticity Impairment in an Alzheimer’s Disease Model

• Published in: Cell reports (Cambridge) 2016-11, Vol.17 (7), p.1819-1831
• Main Authors: Shen, Yang, Tian, Min, Zheng, Yuqiong, Gong, Fei, Fu, Amy K.Y., Ip, Nancy Y.
• Format: Article
• Language: English
• Subjects: alpha-melanoctye-stimulating hormone; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Animals; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; G protein-coupled receptor; GTP-Binding Protein alpha Subunits, Gs - metabolism; hippocampus; Hippocampus - metabolism; Hippocampus - physiopathology; Humans; Long-Term Potentiation; Male; melanocortin receptor; memory loss; Mice, Inbred C57BL; Mice, Transgenic; neural circuit; Neuronal Plasticity; Presenilin-1 - metabolism; pro-opiomelanocortin; Pro-Opiomelanocortin - metabolism; Receptor, Melanocortin, Type 4 - metabolism; Signal Transduction; synapses; synaptic plasticity; Synaptic Transmission
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.043

Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer’s disease (AD). Although pro-opiomelanocortin (POMC)-derived neuropeptides and melanocortin 4 receptor (MC4R) are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3) activate MC4R in the CA1. Suppression of hippocampal MC4R activity in the APP/PS1 transgenic mouse model of AD exacerbates long-term potentiation impairment, which is alleviated by the replenishment of hippocampal POMC/MC4R activity or activation of hippocampal MC4R-coupled Gs signaling. Importantly, MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP)/PKA/cAMP-response element binding protein (CREB)-dependent mechanism. Hence, disruption of this hippocampal POMC/MC4R circuit might contribute to synaptic dysfunction observed in AD, revealing a potential therapeutic target for the disease. [Display omitted] •A functional POMC circuit in the hippocampus connects the CA3 and CA1 regions•Lowered hippocampal MC4R activity reduces synaptic plasticity in an AD mouse model•Activation of MC4R/Gs reverses synaptic plasticity impairment in an AD mouse model•MC4R activation rescues Aβ-induced synaptic defects in a PKA/CREB-dependent manner Shen et al. demonstrate the roles of the hippocampal POMC/MC4R circuit in synaptic plasticity impairment in an Alzheimer’s disease mouse model. Suppression of hippocampal MC4R activation mediates long-term potentiation impairment in the model, whereas stimulation of the circuit restores synaptic functions.