NMDA receptors promote neurogenesis in the neonatal rat subventricular zone following hypoxic-ischemic injury

Abstract

Evidence suggests the involvement of N-methyl-D-aspartate receptors (NMDAR) in the regulation of neurogenesis. Functional properties of NMDAR are strongly influenced by the type of NR2 subunits in the receptor complex. NR2A- and NR2B-containing receptors are expressed in neonatal fore-brain regions, such as the subventricular zone (SVZ). The aim of the present study was to examine the effect of the protein expression of hypoxic-ischemic injury NMDAR subunits 2A and 2B in the SVZ of neonatal rats. Expression of these and other proteins of interest was performed using immunohistochemistry. The results showed that NR2A expression was decreased at 6 h after hypoxic-ischemic injury. By contrast, a significant increase in NR2B expression was observed at 24 h after hypoxic-ischemic injury, induced by the clamping of the right common carotid artery. The functional effect of NMDAR subunits on neurogenesis was also examined by quantifying Nestin and doublecortin (DCX), the microtubule-associated protein expressed only in immature neurons. In addition, the effects of selective non-competitive NMDAR antagonist MK-801 (0.5 mg/kg), NR2B antagonist Ro25-6981 (5 mg/kg), and NR2A antagonist NVP-AAM077 (5 mg/kg) administered 30 min prior to the hypoxic-ischemic injury were examined. The number of Nestin- and DCX-positive cells increased significantly 48 h after hypoxic-ischemic injury, which was reverted by the MK-801 and Ro25-6981 antagonists. Notably, NVP-AAM077 had no significant effect on the expression of Nestin and DCX. In conclusion, the results of the present study demonstrate that hypoxia-ischemia inhibited the expression of NR2A, but promoted the expression of NR2B. Furthermore, NMDAR promoted neurogenesis in the SVZ of neonatal brains.

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…Studies have shown that neonatal hypoxic-ischemic injury is correlated to NMDA receptor-mediated excitotoxicity ( Johnston et al, 2002 ; Wu et al, 2017 ). Furthermore, it has also been proven that after 6 h of hypoxia ischemia, the expression of GluN2A significantly decreases, while the expression of GluN2B exhibits an opposite trend, which reaches a maximum at 24 h after hypoxic ischemia ( Lai et al, 2016 ). This suggests that GluN2A and GluN2B might play different roles in neonatal HIE.…”

“…Hence, they might also play similar roles in HIE. Although most researches have indicated the pro-death role of GluN2B in HIE, there is also evidence that GluN2B could protect neurons against apoptosis during development ( Martel et al, 2009 ; Lai et al, 2016 ). Since the GluN2B-containing NMDA receptor is the dominant subtype in early development, it remains to be determined whether GluN2B plays dual roles in HIE.…”

“…The expression of GluN2A in neonatal brain is relatively low in neonatal brains, and it was found that the expression of GluN2A further decreases after neonatal HIE ( Lai et al, 2016 ). It has been suggested that excessive GluN2A phosphorylation in neonates increases the NMDA receptor-mediated excitotoxicity and affects normal brain function ( Gurd et al, 2002 ).…”

“…It has been suggested that excessive GluN2A phosphorylation in neonates increases the NMDA receptor-mediated excitotoxicity and affects normal brain function ( Gurd et al, 2002 ). Therefore, the downregulation of GluN2A after 6 h of hypoxia ischemia injury might play a protective role ( Lai et al, 2016 ). As mentioned above, after HIE, the SFK is activated and recruited into PSD ( Shao et al, 2017 ).…”

The Memory-Enhancing Effects of Liquiritigenin by Activation of NMDA Receptors and the CREB Signaling Pathway in Mice

“…In addition to these clinical benefits, cognitive enhancements have been observed in declarative and working memory and other cognitive functions in healthy subjects ( Jensen et al ., 2016 ; Veroniki et al ., 2016 ). In this case, potential natural products or their active compounds may promote neurogenesis-associated cell proliferation, migration, differentiation, apoptosis, and synaptogenesis via modulation of NMDARs in the central nervous system (CNS) ( Kim and Oh, 2013 ; Lai et al ., 2016 ).…”