PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex.
PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex.
复制标题
PSD-95缺乏改变了前额叶皮层中的GABA能抑制。
DOI：
10.1016/j.neuropharm.2020.108277
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发表时间：
2020-11-15
影响因子：
4.7
通讯作者：
Gao WJ
中科院分区：
文献类型：
--
作者：
McEachern EP;Coley AA;Yang SS;Gao WJ
突触后密度蛋白-95（Postsynaptic Density Protein-95，PSD-95）是脑内兴奋性突触中的主要支架蛋白，并且是NMDA和AMPA受体的突触成熟的关键调节剂。PSD-95缺陷与神经发育障碍（如自闭症和精神分裂症）中的认知和学习缺陷有关。先前的研究表明，PSD-95缺乏会导致海马兴奋性反应的显著降低。然而，很少有人知道PSD-95缺乏是否会影响γ-氨基丁酸（GABA）能抑制性突触。使用PSD-95转基因小鼠模型（PSD-95+/−），我们研究了PSD-95缺陷如何影响青春期内侧前额叶皮层（mPFC）中GABAA受体的表达和功能。我们的结果显示GABAA受体亚基α1显著增加。相应地，PSD-95+/−小鼠mPFC中锥体神经元中自发抑制性突触后电流（sIPSC）的频率和幅度增加，沿着诱发性IPSC的显著增加，导致PSD-95缺陷小鼠兴奋-抑制平衡的显著转变。此外，PSD-95缺陷通过上调和运输NLGN 2促进抑制性突触功能，并通过tyr-216磷酸化降低GSK 3 β活性。我们的研究提供了新的见解GABA能传输的影响mPFC由于PSD-95缺陷及其潜在的联系与认知和学习障碍相关的精神疾病。
Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95+/−), we studied how PSD-95 deficiency affects GABAA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABAA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95+/− mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with psychiatric disorders.
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.1121251109
发表时间：
2012-10-16
影响因子：
11.1
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通讯作者：
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