Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors.
Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors.
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DOI：
10.1038/s41398-018-0194-7
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发表时间：
2018-08-24
影响因子：
6.8
通讯作者：
Nixon RA
中科院分区：
文献类型：
--
作者：
Yuan A;Veeranna;Sershen H;Basavarajappa BS;Smiley JF;Hashim A;Bleiwas C;Berg M;Guifoyle DN;Subbanna S;Darji S;Kumar A;Rao MV;Wilson DA;Julien JP;Javitt DC;Nixon RA
神经丝蛋白（NFL）最近被发现在突触中发挥独特的作用。已知NFL与N-甲基-d-天冬氨酸（NMDAR）的GluN 1亚基相互作用，并在精神分裂症中减少，但功能后果尚不清楚。在这里，我们研究了NFL与GluN 1的相互作用是否调节突触传递和精神分裂症相关行为。NFL与GluN 1的相互作用通过分子，药理学，电生理，磁共振光谱（MRS）和精神分裂症相关的行为分析进行了评估。NFL缺陷导致NMDAR功能低下表型，包括海马功能异常，如精神分裂症中所见。小鼠中NFL−/−缺失降低树突棘和GluN 1蛋白水平，通过MRS测量升高GluN 1和海马谷氨酸的泛素依赖性周转，并抑制海马长时程增强。NMDAR相关行为也受损，包括幼鼠检索、空间和社会记忆、前脉冲抑制、夜间活动和对NMDAR拮抗剂的反应，而运动缺陷最小。重要的是，将NFL+/-小鼠的NFL部分降低到精神分裂症中局部观察到的水平，诱导了类似但更温和的NMDAR相关突触和行为缺陷。我们的研究结果支持了一个新兴的观点，即中枢神经系统神经丝亚基，包括NFL在本报告中，在神经精神疾病相关的突触中发挥独特的关键作用。
Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-d-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL−/− deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/− mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.
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影响因子：
5.6
作者：
Coumans JV;Palanisamy SK;McFarlane J;Moens PD
通讯作者：
Moens PD
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3.5
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4.5
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通讯作者：
Peralta, Victor
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