Inhibition of NMDA receptors induces delayed neuronal maturation and sustained proliferation of progenitor cells during neocortical development

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Abstract
To elucidate the role of N‐methyl‐D‐aspartate (NMDA) receptors during the early stage of cerebral neocortical development, we investigated the effect of an NMDA receptor antagonist, D(−)‐2‐amino‐5‐phosphonopentanoic acid (D‐APV), on cell migration and proliferation in slice cultures and dissociated primary cultures prepared from rat cerebral neocortex at embryonic Day 17. Pulse‐labeling experiments with 5‐bromo‐2′‐deoxyuridine (BrdU) showed that chronic exposure to D‐APV in slices delayed neuronal migration. Calcium imaging experiments revealed that functional NMDA receptors were expressed in neurons and the treatment with D‐APV delayed neuronal maturation judging from the subunit composition of NMDA receptor subtypes. The results using pulse‐labeling with BrdU indicated that exposure to D‐APV for 3 days induced a clear increase in the number of proliferating progenitor cells in the ventricular zone in neocortical slices. Exposure to D‐APV in primary cultures also increased the proliferation of progenitor cells. The effect of D‐APV on progenitor cell proliferation was possibly mediated through neuronal cells. To elucidate the mechanism of enhanced progenitor cell proliferation induced by D‐APV, we investigated expression of Hes1 and Hes5 mRNA in the ventricular zone of neocortical slices by reverse transcription‐polymerase chain reaction. Tissue exposed to D‐APV for 3 days showed higher expression of Hes1 and Hes5 mRNA than did unexposed control tissue. These results suggest that NMDA receptors expressed in neurons function in neuronal migration and maturation and in the proliferation of progenitor cells.