Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, 310027 Hangzhou, People's Republic of China.
Center of Stem Cell and Regenerative Medicine, and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, 310058 Hangzhou, People's Republic of China.
J Neurosci. 2023 Apr 19;43(16):2822-2836. doi: 10.1523/JNEUROSCI.1886-22.2023. Epub 2023 Mar 6.
Metabotropic glutamate receptor 2 (GRM2) is highly expressed in hippocampal dentate granule cells (DGCs), regulating synaptic transmission and hippocampal functions. Newborn DGCs are continuously generated throughout life and express GRM2 when they are mature. However, it remained unclear whether and how GRM2 regulates the development and integration of these newborn neurons. We discovered that the expression of GRM2 in adult-born DGCs increased with neuronal development in mice of both sexes. Lack of GRM2 caused developmental defects of DGCs and impaired hippocampus-dependent cognitive functions. Intriguingly, our data showed that knockdown of resulted in decreased b/c-Raf kinases and paradoxically led to an excessive activation of MEK/ERK1/2 pathway. Inhibition of MEK ameliorated the developmental defects caused by knockdown. Together, our results indicate that GRM2 is necessary for the development and functional integration of newborn DGCs in the adult hippocampus through regulating the phosphorylation and activation state of MEK/ERK1/2 pathway. Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature dentate granule cells (DGCs) in the hippocampus. It remains unclear whether GRM2 is required for the development and integration of adult-born DGCs. We provided and evidence to show that GRM2 regulates the development of adult-born DGCs and their integration into existing hippocampal circuits. Lack of GRM2 in a cohort of newborn DGCs impaired object-to-location memory in mice. Moreover, we revealed that GRM2 knockdown paradoxically upregulated MEK/ERK1/2 pathway by suppressing b/c-Raf in developing neurons, which is likely a common mechanism underlying the regulation of the development of neurons expressing GRM2. Thus, Raf/MEK/ERK1/2 pathway could be a potential target for brain diseases related to GRM2 abnormality.
代谢型谷氨酸受体 2（GRM2）在海马齿状回颗粒细胞（DGCs）中高度表达，调节突触传递和海马功能。新生的 DGC 会在一生中不断产生，并在成熟时表达 GRM2。然而，GRM2 是否以及如何调节这些新生神经元的发育和整合仍不清楚。我们发现，雄性和雌性小鼠成年新生 DGC 中的 GRM2 表达随着神经元的发育而增加。GRM2 的缺失导致 DGC 的发育缺陷，并损害了海马依赖的认知功能。有趣的是，我们的数据表明，下调导致 b/c-Raf 激酶减少，反而导致 MEK/ERK1/2 通路过度激活。MEK 的抑制改善了由 下调引起的发育缺陷。总之，我们的结果表明，GRM2 通过调节 MEK/ERK1/2 通路的磷酸化和激活状态，对于成年海马中新生成的 DGC 的发育和功能整合是必需的。代谢型谷氨酸受体 2（GRM2）在海马中的成熟齿状回颗粒细胞（DGCs）中高度表达。GRM2 是否需要参与成年新生 DGC 的发育和整合仍不清楚。我们提供了 和 证据，表明 GRM2 调节成年新生 DGC 的发育及其整合到现有的海马回路中。缺乏 GRM2 会损害新生 DGC 队列中小鼠的物体定位记忆。此外，我们揭示了 GRM2 下调通过抑制发育神经元中的 b/c-Raf 使 MEK/ERK1/2 通路反常地上调，这可能是调节表达 GRM2 的神经元发育的共同机制。因此，Raf/MEK/ERK1/2 通路可能是与 GRM2 异常相关的脑疾病的潜在靶点。
