Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.
Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.
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DOI：
10.1016/j.neuropharm.2015.02.013
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发表时间：
2015-06
影响因子：
4.7
通讯作者：
Dravid SM
中科院分区：
文献类型：
--
作者：
Gupta SC;Yadav R;Pavuluri R;Morley BJ;Stairs DJ;Dravid SM
谷氨酸δ-1（GluD 1）受体在前脑中高度表达。我们之前已经表明，GluD 1的丢失导致小鼠的社交和认知缺陷，然而，其在突触发育和神经传递中的作用仍然知之甚少。在这里，我们报告说，GluD 1是丰富的内侧前额叶皮层（mPFC）和GluD 1基因敲除小鼠表现出较高的树突棘数，更大的兴奋性神经传递，以及更多的突触在mPFC。此外，在调节脊柱动力学的LIMK 1-cofilin信号传导中的异常，以及在GluD 1敲除小鼠的mPFC中观察到GluN 2A/GluN 2B表达的较低比率。对GluD 1敲除的CA 1海马体的分析同样表明存在更高的棘数目和突触以及改变的LIMK 1-cofilin信号传导。我们发现，全身给予高剂量的N-甲基-d-天冬氨酸（NMDA）受体部分激动剂d-环丝氨酸（DCS），而不是低剂量，和GluN 2B选择性抑制剂Ro-25-6981部分正常化LIMK 1-cofilin信号传导的异常，并减少mPFC中多余的棘数。高剂量DCS和GluN 2B抑制剂的分子效应与其减少GluD 1敲除小鼠中较高刻板行为和抑郁样行为的能力相关。总之，这些研究结果表明，在皮层和海马体的正常脊柱发育中，GluD 1是至关重要的。此外，这些结果确定了抑制含GluN 2B受体作为减少过量树突棘和刻板行为的机制，这在某些神经发育障碍中可能具有治疗价值。
The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2Bcontaining receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders.
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