Targeting Metabotropic Glutamate Receptor 7 Promotes Neurogenesis

Abstract Human neural progenitor cells (hNPCs) have been reported to exist in various regions of the central nervous system (CNS) throughout the lifespan and to maintain homeostasis of the CNS. The endogenous NPC pools as well as their function decline during aging, neurodegeneration, or brain damage; therefore, supplementation with hNPCs or enhancement of the potency of endogenous NPCs could lead to potential treatments for these diseases. Here, we showed that 2-phospho-L-ascorbic acid (Asc-2P) promoted hNPC proliferation and differentiation by maintaining mitochondrial glycolysis under growth factor-lacking conditions. Upregulation of metabotropic glutamate receptor 7 (mGluR7) expression by Asc-2P treatment and retention of mGluR7 on the plasma membrane by the specific group III mGluR antagonist alpha-methylserine-O-phosphate (MSOP) promoted the formation of fibroblast growth factor receptor 1 (FGFR1) and mGluR7 complex on the cytomembrane, thereby enhanced the phosphorylation and activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), maintained mitochondrial glycolysis, thus enhanced hNPC proliferation and differentiation in vitro and in vivo. Furthermore, Asc-2P treatment alleviated pathogenesis and related cognitive decline in an Alzheimer’s disease mouse model. Taken together, our findings indicated that modulation of mGluR7 by Asc-2P and/or its antagonists could be promising pharmaceutical and therapeutic options against neurodegeneration and related diseases.