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

Jiao Ma1,2, Zhechun Hu3, Huimin Yue1,3

  • 1Department 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.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|March 6, 2023
PubMed
Summary

Metabotropic glutamate receptor 2 (GRM2) is crucial for developing new hippocampal neurons and cognitive functions. Its absence disrupts neuron development and impairs memory by altering the MEK/ERK1/2 pathway.

Keywords:
GRM2MEK/ERK1/2 pathwayadult neurogenesisadult-born dentate granule cellshippocampusobject-to-location recognition

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature hippocampal dentate granule cells (DGCs).
  • The role of GRM2 in the development and integration of adult-born DGCs remains largely unknown.
  • Newborn DGCs are continuously generated and express GRM2 upon maturation.

Purpose of the Study:

  • To investigate the function of GRM2 in the development and integration of adult-born DGCs.
  • To elucidate the molecular mechanisms by which GRM2 regulates neurogenesis.
  • To determine the impact of GRM2 on hippocampus-dependent cognitive functions.

Main Methods:

  • Utilized mouse models with GRM2 deficiency (knockdown).
  • Performed in vivo and in vitro experiments to assess DGC development and function.
  • Analyzed the MEK/ERK1/2 signaling pathway activation and Raf kinase levels.

Main Results:

  • GRM2 expression increases with neuronal development in adult-born DGCs.
  • GRM2 deficiency leads to DGC developmental defects and impaired hippocampus-dependent memory.
  • GRM2 knockdown paradoxically increases MEK/ERK1/2 pathway activation via suppressed b/c-Raf kinases.
  • MEK inhibition rescued developmental deficits in GRM2-deficient DGCs.

Conclusions:

  • GRM2 is essential for the proper development and functional integration of newborn DGCs in the adult hippocampus.
  • GRM2 regulates the MEK/ERK1/2 pathway, suggesting a novel mechanism for neurodevelopmental control.
  • The Raf/MEK/ERK1/2 pathway represents a potential therapeutic target for GRM2-related neurological disorders.