A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.
A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.
复制标题
突触后AMPK→P21激活的激酶途径驱动禁食诱导的AGRP神经元中的突触可塑性。
DOI：
10.1016/j.neuron.2016.05.025
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发表时间：
2016-07-06
期刊：
影响因子：
16.2
通讯作者：
Lowell BB
中科院分区：
文献类型：
--
作者：
Kong D;Dagon Y;Campbell JN;Guo Y;Yang Z;Yi X;Aryal P;Wellenstein K;Kahn BB;Sabatini BL;Lowell BB
AMP活化蛋白激酶（AMPK）在调节食物摄取中起重要作用。然而，下游AMPK底物和神经生物学机制对此负责，是不明确的。弓状核中表达Agouti相关肽（AgRP）的神经元调节饥饿。他们的饮食习惯，也是一种饮食习惯，一旦吃到饱，就会变得更糟。AgRP神经元活动受状态依赖性突触可塑性调节;禁食增加树突棘和兴奋性突触活动，进食则相反。然而，这背后的信号机制也是未知的。使用神经元特异性的方法来测量和操纵激酶活性，特别是在AgRP神经元内，我们建立了禁食增加AMPK活性在AgRP神经元，增加AMPK活性在AgRP神经元是必要的和足够的禁食诱导的脊髓和兴奋性突触活动，和AMPK磷酸化的目标介导这种可塑性是p21激活激酶。这为AMPK调节能量平衡和AgRP神经元状态依赖性可塑性提供了信号和神经生物学基础。
AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill-defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity; fasting increases dendritic spines and excitatory synaptic activity, feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity.