Involvement of metabotropic glutamate receptor 5 signaling in activity‐related proliferation of adult hippocampal neural stem cells

Abstract

Adult hippocampal neural stem cells can be activated by hippocampal neural activities. When focal cerebral ischemia, known as middle cerebral artery occlusion (MCAO), occurs, neural stem cells are activated to promote their proliferation. However, the mechanism by which these cells are activated is still unclear. Here, we indicate the involvement of metabotropic glutamate receptor 5 (mGluR5) signaling in neural stem cells in their activity-related proliferation after MCAO. We found mGluR5 molecules on neural stem cells by using calcium imaging. We detected the activation of neural stem cells by adding the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine. On a hippocampal slice, the activation of neural stem cells to promote their proliferation was initiated by theta-burst electrical stimulation at the perforant pathway, and this activation was significantly blocked by an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP). In addition to this, the injection of the blood-brain barrier-permeable mGluR5 agonist 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide into live mice promoted the proliferation of neural stem cells. Moreover, in vivo theta-burst electrical stimulation induced proliferation of neural stem cells. A chronic field recording study showed that the activity of the hippocampal formation was elevated after MCAO. Finally, we observed that the mGluR5 antagonist MPEP significantly blocked the stimulated proliferation of neural stem cells induced by MCAO, by blocking mGluR5 signaling. Our results suggest that glutamates released by the elevated neural activities after MCAO may trigger mGluR5 signaling in neural stem cells to promote their proliferation.

Glutamate Increases In Vitro Survival and Proliferation and Attenuates Oxidative Stress-Induced Cell Death in Adult Spinal Cord-Derived Neural Stem/Progenitor Cells via Non-NMDA Ionotropic Glutamate Receptors

“…[37] The class I mGluR5 receptor has also been implicated in promoting proliferation of human NSPCs [38] and adult hippocampal neural stem cells. [39] An analysis of other metabotropic glutamate receptors in the context of adult spinal cord NSPCs thus warrants further investigation. Given the low rates of survival of these cells after transplantation, determining ways to promote their survival is essential.…”

Regulation of neurogenesis by calcium signaling

“…GABAergic signaling appears to be paired with increased expression of voltage-gated Ca 2+ channels and loss of either excitatory GABAergic transmission or voltage-gated Ca 2+ channels lead to diminished proliferation [148,149], highlighting the importance of this transition for progenitor function. In addition, glutamatergic signaling involving both metabotropic glutamate receptors [150] as well as NMDA receptors is implicated in the proliferation of DCX positive late stage progenitors [122]. Both NMDA receptor blockade as well as inhibition of L-type Ca 2+ channels impair proliferation of hippocampal progenitors [122], suggesting a growing importance of activity dependent pathways for nurturing and tuning the proliferative response.…”

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

“…Indeed, extracellular signals that regulate survival and integration, such as the neurotrophic factors BDNF, FGF-2 and NT-3 [12-14], or the neurotransmitters GABA [12,15,16] and Glutamate [17,18], require intracellular modulators to transduce these signals. In this sense, it has been described the role of Prox1 in transducing Wnt singaling [19], CREB signaling in GABA-mediated excitation [20] or NFATc4 for BDNF-driven survival signaling [21] in adult hippocampal neurogenesis (AHN).…”