2. Academic Validation
  3. GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway

GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway

  • J Neurosci. 2023 Apr 19;43(16):2822-2836. doi: 10.1523/JNEUROSCI.1886-22.2023.
Jiao Ma 1 2,  Zhechun Hu 3,  Huimin Yue 1 3,  Yujian Luo 1 3,  Chao Wang 3,  Xuan Wu 2,  Yan Gu 4 5,  Lang Wang 6 3
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 School of Brain Science and Brain Medicine, Zhejiang University, 310058 Hangzhou, People's Republic of China.
  • 4 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 [email protected] [email protected].
  • 5 MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University, 310058 Hangzhou, People's Republic of China.
  • 6 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 [email protected] [email protected].
PMID: 36878727 DOI: 10.1523/JNEUROSCI.1886-22.2023
Abstract

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 Grm2 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 Grm2 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.SIGNIFICANCE STATEMENT 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 in vivo and in vitro 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.

Keywords

GRM2; MEK/ERK1/2 pathway; adult neurogenesis; adult-born dentate granule cells; hippocampus; object-to-location recognition.

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