Machine Learning algorithm unveils glutamatergic alterations in the post-mortem schizophrenia brain.
Machine Learning algorithm unveils glutamatergic alterations in the post-mortem schizophrenia brain.
复制标题
DOI：
10.1038/s41537-022-00231-1
复制
发表时间：
2022-02-25
期刊：
影响因子：
--
通讯作者：
Usiello A
中科院分区：
文献类型：
--
作者：
De Rosa A;Fontana A;Nuzzo T;Garofalo M;Di Maio A;Punzo D;Copetti M;Bertolino A;Errico F;Rampino A;de Bartolomeis A;Usiello A
精神分裂症是一种突触可塑性和异常连接的障碍，其中谷氨酸突触的主要功能障碍已被提出。然而，一个多层次的方法来解决精神分裂症中谷氨酸信号的相互作用分子的不同集群仍然缺乏。我们调查了精神分裂症患者和非精神病对照的死后背外侧前额叶皮层（DLPFC）和海马中神经活性D-和L-氨基酸（L-谷氨酸，D-丝氨酸，甘氨酸，L-天冬氨酸，D-天冬氨酸）的水平。此外，通过定量RT-PCR和蛋白质印迹法，我们分别分析了突触前和突触后参与突触功能的关键分子（包括谷氨酸受体）的mRNA和蛋白质水平（NMDA，AMPA，代谢型），它们相互作用的支架蛋白（PSD-95，Homer 1b/c），质膜和囊泡谷氨酸转运蛋白（EAAT 1，EAAT 2，VGluT 1，VGluT 2），参与谷氨酸依赖性GABA神经递质合成的酶（GAD 65和67），或在突触后NMDA受体介导的信号传导（CAMKIIα）和突触前标志物突触蛋白-1。单变量分析显示，没有一个被调查的分子是不同的代表精神分裂症患者的死后DLPFC和海马，与对照组相比。尽管如此，多变量假设驱动的分析显示，精神分裂症的存在显着影响的变化，神经活性氨基酸水平和谷氨酸相关的突触元件。此外，机器学习无假设揭示了其他有区别的分子簇，一个在DLPFC中，另一个在海马体中。总的来说，虽然证实了谷氨酸能突触在精神分裂症的分子病理生理学中的关键作用，但我们报告了包含谷氨酸突触元素的分子特征，这些分子特征能够区分精神分裂症患者和正常人。
Schizophrenia is a disorder of synaptic plasticity and aberrant connectivity in which a major dysfunction in glutamate synapse has been suggested. However, a multi-level approach tackling diverse clusters of interacting molecules of the glutamate signaling in schizophrenia is still lacking. We investigated in the post-mortem dorsolateral prefrontal cortex (DLPFC) and hippocampus of schizophrenia patients and non-psychiatric controls, the levels of neuroactive d- and l-amino acids (l-glutamate, d-serine, glycine, l-aspartate, d-aspartate) by HPLC. Moreover, by quantitative RT-PCR and western blotting we analyzed, respectively, the mRNA and protein levels of pre- and post-synaptic key molecules involved in the glutamatergic synapse functioning, including glutamate receptors (NMDA, AMPA, metabotropic), their interacting scaffolding proteins (PSD-95, Homer1b/c), plasma membrane and vesicular glutamate transporters (EAAT1, EAAT2, VGluT1, VGluT2), enzymes involved either in glutamate-dependent GABA neurotransmitter synthesis (GAD65 and 67), or in post-synaptic NMDA receptor-mediated signaling (CAMKIIα) and the pre-synaptic marker Synapsin-1. Univariable analyses revealed that none of the investigated molecules was differently represented in the post-mortem DLPFC and hippocampus of schizophrenia patients, compared with controls. Nonetheless, multivariable hypothesis-driven analyses revealed that the presence of schizophrenia was significantly affected by variations in neuroactive amino acid levels and glutamate-related synaptic elements. Furthermore, a Machine Learning hypothesis-free unveiled other discriminative clusters of molecules, one in the DLPFC and another in the hippocampus. Overall, while confirming a key role of glutamatergic synapse in the molecular pathophysiology of schizophrenia, we reported molecular signatures encompassing elements of the glutamate synapse able to discriminate patients with schizophrenia and normal individuals.
登录
查看更多内容
影响因子：
14.5
作者：
Chen, Qiang;Ursini, Gianluca;Weinberger, Daniel R.
通讯作者：
Weinberger, Daniel R.
影响因子：
5
作者：
Cole, Stephen R.;Hernan, Miguel A.
通讯作者：
Hernan, Miguel A.
DOI：
10.1176/appi.ajp.2020.20101481
发表时间：
2020-12-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Coyle JT;Ruzicka WB;Balu DT
通讯作者：
Balu DT
影响因子：
3.7
作者：
Crabtree GW;Gogos JA
通讯作者：
Gogos JA
影响因子：
4.7
作者：
Caravaggio，Fernando;Iwata，Yusuke;Graff-Guerrero，Ariel
通讯作者：
Graff-Guerrero，Ariel