14-3-3 proteins promote synaptic localization of N-methyl d-aspartate receptors (NMDARs) in mouse hippocampal and cortical neurons.
14-3-3 proteins promote synaptic localization of N-methyl d-aspartate receptors (NMDARs) in mouse hippocampal and cortical neurons.
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DOI：
10.1371/journal.pone.0261791
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Lee GS;Zhang J;Wu Y;Zhou Y
精神分裂症的核心发病机制之一被认为是谷氨酸能突触传递功能障碍，特别是N-甲基-D-天冬氨酸受体(NMDAR)功能低下。此前，我们发现14-3-3功能性基因敲除小鼠表现出与精神分裂症相关的行为，伴随着前脑兴奋性神经元突触NMDAR的减少。为了研究14-3-3蛋白如何调节NMDAR的突触定位，我们研究了14-3-3抑制原代神经元时突触NMDAR水平的变化。14-3-3蛋白抑制剂(Difopein)在原代谷氨酸能皮质和海马神经元中的表达导致含有NMDAR的突触点数减少，包括GluN1、GluN2A或GluN2B亚单位。在异种细胞中，14-3-3蛋白增强了这些NMDAR亚基的表面表达。此外，我们还发现14-3-3ζ和ε亚型通过与GluN2A和GluN2B亚基结合而与NMDAR相互作用。综上所述，我们的结果表明，14-3-3蛋白通过促进NMDAR亚单位GluN1、GluN2A和GluN2B的表面递送，在NMDAR突触运输中发挥关键作用。由于NMDAR功能低下被认为是精神分裂症症状进展的汇聚点，对这些信号通路的进一步研究可能有助于理解14-3-3蛋白的功能障碍如何导致NMDAR功能低下并导致精神分裂症相关行为。
One of the core pathogenic mechanisms for schizophrenia is believed to be dysfunction in glutamatergic synaptic transmissions, particularly hypofunction of N-methyl d-aspartate receptors (NMDARs). Previously we showed that 14-3-3 functional knockout mice exhibit schizophrenia-associated behaviors accompanied by reduced synaptic NMDARs in forebrain excitatory neurons. To investigate how 14-3-3 proteins regulate synaptic localization of NMDARs, here we examined changes in levels of synaptic NMDARs upon 14-3-3 inhibition in primary neurons. Expression of 14-3-3 protein inhibitor (difopein) in primary glutamatergic cortical and hippocampal neurons resulted in lower number of synaptic puncta containing NMDARs, including the GluN1, GluN2A, or GluN2B subunits. In heterologous cells, 14-3-3 proteins enhanced surface expression of these NMDAR subunits. Furthermore, we identified that 14-3-3ζ and ε isoforms interact with NMDARs via binding to GluN2A and GluN2B subunits. Taken together, our results demonstrate that 14-3-3 proteins play a critical role in NMDAR synaptic trafficking by promoting surface delivery of NMDAR subunits GluN1, GluN2A, and GluN2B. As NMDAR hypofunctionality is known to act as a convergence point for progression of symptoms of schizophrenia, further studies on these signaling pathways may help understand how dysfunction of 14-3-3 proteins can cause NMDAR hypofunctionality and lead to schizophrenia-associated behaviors.
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DOI：
10.3791/2270
发表时间：
2010-11-16
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ippolito, Dominic M;Eroglu, Cagla
通讯作者：
Eroglu, Cagla
DOI：
10.1006/bbrc.1993.1796
发表时间：
1993-07-15
影响因子：
3.1
作者：
FURUKAWA, Y;IKUTA, N;ICHIMURA, T
通讯作者：
ICHIMURA, T
影响因子：
5.4
作者：
Graham, Kourtney;Zhang, Jiajing;Zhou, Yi
通讯作者：
Zhou, Yi
影响因子：
4
作者：
Heusser, Katja;Yuan, Hebao;Schwappach, Blanche
通讯作者：
Schwappach, Blanche
影响因子：
64.8
作者：
FANTL, WJ;MUSLIN, AJ;WILLIAMS, LT
通讯作者：
WILLIAMS, LT