Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
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DOI：
10.1371/journal.pbio.1001820
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发表时间：
2014-03
期刊：
影响因子：
9.8
通讯作者：
Pieters J
中科院分区：
文献类型：
--
作者：
Jayachandran R;Liu X;Bosedasgupta S;Müller P;Zhang CL;Moshous D;Studer V;Schneider J;Genoud C;Fossoud C;Gambino F;Khelfaoui M;Müller C;Bartholdi D;Rossez H;Stiess M;Houbaert X;Jaussi R;Frey D;Kammerer RA;Deupi X;de Villartay JP;Lüthi A;Humeau Y;Pieters J
进化上保守的蛋白 Coronin 1 是激活大脑中环 AMP 信号通路所必需的，对认知和行为很重要。认知和行为障碍被认为是神经元功能障碍的结果，但潜在的分子缺陷仍然很大程度上未知。参与神经元功能调节的重要信号通路是环AMP/蛋白激酶A通路。我们在此展示了 Coronin 1 在环 AMP/PKA 信号传导调节中的重要作用，该蛋白在与神经行为功能障碍相关的基因组区域中编码。我们发现 Coronin 1 在兴奋性神经元中特异性表达，但在抑制性神经元中不表达，Coronin 1 缺乏会导致兴奋性突触丧失和严重的神经行为障碍，包括焦虑减少、社交缺陷、攻击性增加和学习缺陷。对杏仁核兴奋性突触传递的电生理学分析表明，coronin 1 对于环 AMP 蛋白激酶 A 依赖性突触前可塑性至关重要。我们进一步表明，在细胞表面刺激后，coronin 1 与 G 蛋白亚型 Gαs 相互作用，刺激 cAMP/PKA 通路。 Coronin 1 的缺失或 Coronin 1 突变体的表达无法与 Gαs 相互作用，导致 cAMP 信号传导显着减少。引人注目的是，通过体内输注可渗透膜的 cAMP 类似物，Coronin 1 缺陷小鼠的突触可塑性和行为缺陷得以恢复。这些结果共同表明 Coronin 1 通过其促进 cAMP/PKA 依赖性突触可塑性的活性对认知和行为很重要，并且可能为解析神经行为过程中涉及的信号转导途径开辟新途径。记忆和行为取决于大脑中信号的正确转导，但潜在的分子机制仍然很大程度上未知。 Coronin 1 是一个高度保守的蛋白质家族的成员，尽管它的基因位于与小鼠和人类神经行为功能障碍相关的染色体区域，但它从未被直接归因于大脑中的特定功能。在这里，我们证明 Coronin 1 通过调节环 AMP (cAMP) 信号通路在认知和行为中发挥重要作用。我们发现，当细胞表面受体被激活时，Coronin 1 会刺激 cAMP 的产生和蛋白激酶 A 的激活。Coronin 1 缺乏会导致兴奋性突触的严重功能缺陷。此外，在小鼠和人类中，coronin 1 的缺失或突变会导致严重的神经行为缺陷，包括社交缺陷、攻击性增加和学习障碍。引人注目的是，用膜渗透性 cAMP 类似物治疗可恢复缺乏 Coronin 1 的小鼠的突触可塑性和行为缺陷。这项工作不仅表明 Coronin 1 在神经行为中的关键作用，而且还确定了 Coronin 家族在调节细胞内信号传递中的作用。
The evolutionarily conserved protein coronin 1 is needed for activating the cyclic AMP signaling pathway in the brain and is important for cognition and behavior. Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic–AMP–protein kinase A–dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1–deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes. Memory and behavior depend on the proper transduction of signals in the brain, but the underlying molecular mechanisms remain largely unknown. Coronin 1 is a member of a highly conserved family of proteins, and although its gene lies in a chromosome region associated with neurobehavioral dysfunction in mice and men, it has never been directly ascribed a specific function in the brain. Here we show that coronin 1 plays an important role in cognition and behavior by regulating the cyclic AMP (cAMP) signaling pathway. We find that when cell surface receptors are activated, coronin 1 stimulates cAMP production and activation of protein kinase A. Coronin 1 deficiency resulted in severe functional defects at excitatory synapses. Furthermore, in both mice and humans, deletion or mutation of coronin 1 causes severe neurobehavioral defects, including social deficits, increased aggression, and learning disabilities. Strikingly, treatment with a membrane-permeable analogue of cAMP restored synaptic plasticity and behavioral defects in mice lacking coronin 1. Together this work not only shows a critical role for coronin 1 in neurobehavior but also defines a role for the coronin family in regulating the transmission of signals within cells.
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