Melanocortin-4 Receptor Regulates Hippocampal Synaptic Plasticity through a Protein Kinase A-Dependent Mechanism
Melanocortin-4 Receptor Regulates Hippocampal Synaptic Plasticity through a Protein Kinase A-Dependent Mechanism
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DOI：
10.1523/jneurosci.3282-12.2013
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发表时间：
2013-01-09
影响因子：
5.3
通讯作者：
Ip, Nancy Y.
中科院分区：
文献类型：
--
作者：
Shen, Yang;Fu, Wing-Yu;Ip, Nancy Y.
学习和记忆需要海马结构和功能突触可塑性的协调调节。虽然神经肽α-黑素细胞刺激激素α-MSH与记忆获得和保持有关，但其同源受体黑皮质素-4受体（MC 4 R）在海马依赖性突触可塑性中的功能作用尚未研究。在这项研究中，我们报告说，激活MC 4 R增强突触可塑性，通过调节树突棘形态和丰富的AMPA受体。我们发现，激活突触后MC 4 R增加了成熟的树突棘的数量，并增强了AMPA受体亚基GluA 1的表面表达，导致含GluA 1的AMPA受体的突触积累。此外，MC 4 R通过G α（s）-cAMP/PKA依赖性方式在Ser 845处磷酸化GluA 1来刺激表面GluA 1运输。阻断蛋白激酶A（PKA）信号传导可消除MC 4 R介导的神经传递增强和海马长时程增强。重要的是，MC 4 R激动剂的体内应用增加了小鼠海马CA 1区的LTP。这些发现揭示了海马MC 4 R在结构和功能可塑性的调节中起着关键作用。
Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, alpha-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluA1, resulting in synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulates surface GluA1 trafficking through phosphorylation of GluA1 at Ser845 in a G alpha(s)-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CA1 region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity.