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PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation
Communications Biology ( IF 5.9 ) Pub Date : 2020-11-26 , DOI: 10.1038/s42003-020-01435-w
Hiroki Yasuda 1, 2 , Hikaru Yamamoto 3 , Kenji Hanamura 4 , Mona Mehruba 5 , Toshio Kawamata 6 , Hiromi Morisaki 7 , Masaaki Miyamoto 7 , Shinji Takada 8 , Tomoaki Shirao 4 , Yoshitaka Ono 3, 7 , Hideyuki Mukai 3, 5
Affiliation  

Abnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.



中文翻译:

PKN1通过抑制神经元谷氨酸转运蛋白的活化而抑制mGluR依赖性沉默,从而促进突触成熟。

代谢型谷氨酸受体(mGluR)活性异常可能导致脑部疾病;但是,其法规尚未完全了解。在这里,我们报告蛋白质激酶N1(PKN1),主要在大脑神经元中表达的一种蛋白激酶,通过上调神经元谷氨酸转运蛋白,兴奋性氨基酸转运蛋白3(EAAT3)来使第1组mGluR功能正常化,并支持突触激活。敲除大脑中主要的PKN1亚型PKN1a,可以消除发育中的海马体中异常的输入非特异性mGluR依赖性长期抑郁症(mGluR-LTD)和AMPA受体(AMPAR)沉默。通过抑制野生型小鼠中的谷氨酸转运蛋白来模拟mGluR-LTD。敲除PKN1a会降低海马EAAT3的表达,而PKN1的抑制则会减少谷氨酸通过EAAT3的摄取。也,突触传递不成熟;与野生型小鼠相比,PKN1a基因敲除小鼠的沉默突触更多,而突触后密度较小的棘较少。因此,PKN1通过上调EAAT3的表达在突触成熟的调节中起关键作用。

更新日期:2020-11-27
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