Functional roles of melanocortin-4 receptor in hippocampal synaptic plasticity

Abstract

Learning and memory require the orchestrated regulation of both neuronal connections and synaptic strength in the hippocampus. While neuropeptide alpha melanocyte-stimulating hormone (α-MSH) is implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in the hippocampus remains unexplored. This study revealed that MC4R activation is important for hippocampal synaptic plasticity via the regulation of dendritic spine morphology as well as the abundance of postsynaptic glutamate receptors. Silencing MC4R in rat hippocampal neurons reduced mature dendritic spines and increased immature spines. Meanwhile, MC4R activation increased the surface expression of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype glutamate receptor, which ultimately enhanced the synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulated the surface trafficking of GluA1 trafficking via protein phosphorylation at Ser845 in a Gαs-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolished the MC4R-mediated enhancement of neurotransmission and hippocampal synaptic plasticity of long-term potentiation LTP in brain slices. Importantly, the delivery of MC4R agonist in vivo increases LTP in the hippocampal cornu ammonis area 1 (CA1) region. These findings collectively reveal that hippocampal MC4R is critical for the regulation of structural and functional plasticity. Alzheimer’s disease (AD), which is characterized by cognitive decline, has emerged as a disease of synaptic failure. The results show that MC4R signaling is important for mediating the impairment of synaptic plasticity in the hippocampus of AD mouse models. In addition, the activation of MC4R signaling reverses the synaptic impairment induced by soluble amyloid-β peptide oligomers (Aβ), which are believed to be major toxic agents in the disease. Thus, the present findings imply the therapeutic potential of MC4R signaling for cognitive dysfunctions associated with AD.

Date of Award	2013
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology