THESIS
2013
iv leaves, v-xvii, 133 pages : illustrations (some color) ; 30 cm
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-isoxazolep...[
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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.
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