Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors
Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors
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DOI：
10.1007/s00406-016-0728-z
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发表时间：
2018-02-01
影响因子：
4.7
通讯作者：
Inta, Dragos
中科院分区：
文献类型：
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作者：
Luoni, Alessia;Gass, Peter;Inta, Dragos
支持所谓的神经元能假说的证据包括从NMDA受体功能减退到特定大脑结构中兴奋性和抑制性回路之间的不平衡。代谢型受体在神经元兴奋性和突触可塑性的调节中起主要作用。在这里，我们研究，使用qRT-PCR和蛋白质印迹，在海马和前额叶/额叶皮质（PFC/FC）的小鼠与代谢型谷氨酸受体5（mGlu 5）的基因缺失的后果，解决GABA能和谷氨酸能系统的关键组成部分。我们发现，mGlu 5敲除（KO）小鼠显示出reelin，GAD 65，GAD 67和小清蛋白mRNA水平的显着降低，这是PFC/FC的特异性，这是由雄性KO小鼠中蛋白质水平的显着降低所证实的。接下来，我们分析了主要的NMDA和AMPA受体亚基，即GluN 1，GluN 2A，GluN 2B和GluA 1，我们发现mGlu 5缺失决定了它们的mRNA水平显着降低，也在海马中，两种性别之间存在差异。我们的数据表明，神经化学异常冲击谷氨酸能和GABA能系统可能是负责与mGlu 5基因敲除动物的行为表型，并指出这些分子的球员的神经精神疾病，如精神分裂症的发展密切的相互作用。这些数据可能有助于更好地了解mGlu 5的改变参与的兴奋和抑制的分子之间的不平衡，潜在的精神分裂症样表型的出现，并了解潜在的mGlu 5调制器在扭转赤字特征的精神分裂症的病理。
The evidence underlying the so-called glutamatergic hypothesis ranges from NMDA receptor hypofunction to an imbalance between excitatory and inhibitory circuits in specific brain structures. Among all glutamatergic system components, metabotropic receptors play a main role in regulating neuronal excitability and synaptic plasticity. Here, we investigated, using qRT-PCR and western blot, consequences in the hippocampus and prefrontal/frontal cortex (PFC/FC) of mice with a genetic deletion of the metabotropic glutamate receptor 5 (mGlu5), addressing key components of the GABAergic and glutamatergic systems. We found that mGlu5 knockout (KO) mice showed a significant reduction of reelin, GAD65, GAD67 and parvalbumin mRNA levels, which is specific for the PFC/FC, and that is paralleled by a significant reduction of protein levels in male KO mice. We next analyzed the main NMDA and AMPA receptor subunits, namely GluN1, GluN2A, GluN2B and GluA1, and we found that mGlu5 deletion determined a significant reduction of their mRNA levels, also within the hippocampus, with differences between the two genders. Our data suggest that neurochemical abnormalities impinging the glutamatergic and GABAergic systems may be responsible for the behavioral phenotype associated with mGlu5 KO animals and point to the close interaction of these molecular players for the development of neuropsychiatric disorders such as schizophrenia. These data could contribute to a better understanding of the involvement of mGlu5 alterations in the molecular imbalance between excitation and inhibition underlying the emergence of a schizophrenic-like phenotype and to understand the potential of mGlu5 modulators in reversing the deficits characterizing the schizophrenic pathology.