GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.
GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.
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DOI：
10.1016/j.neuron.2017.02.031
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发表时间：
2017-03-22
期刊：
影响因子：
16.2
通讯作者：
Huganir RL
中科院分区：
文献类型：
--
作者：
Chiu SL;Diering GH;Ye B;Takamiya K;Chen CM;Jiang Y;Niranjan T;Schwartz CE;Wang T;Huganir RL
学习依赖于经验对大脑中突触效力和神经元连通性的修改。我们为循环内体蛋白GRASP1在谷氨酸能突触功能和动物行为中的生理作用提供了直接证据。缺乏GRASP1的小鼠表现出异常的兴奋性突触数量、突触可塑性和海马依赖的学习和记忆，这是由于学习诱导的突触AMPAR掺入失败所致。我们从智能障碍(ID)患者中发现了两个GRASP1点突变，它们对AMPAR循环和谷氨酸去化诱导的结构和功能可塑性显示出收敛的干扰作用。野生型GRASP1，而不是ID突变体，拯救了Grasp1基因敲除小鼠海马CA1神经元中的脊椎丢失。综上所述，这些结果表明在体内AMPAR依赖的突触功能和神经元连接中需要正常的内体循环功能，并提示GRASP1在人类认知障碍的病理生理学中可能发挥作用。
Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescues spine loss in hippocampal CA1 neurons of Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders.