NMDA and benzodiazepine receptors have synergistic and antagonistic effects on precursor cells in adult hippocampal neurogenesis

We studied how the noncompetitive NMDA receptor antagonist MK801 affected different stages of adult hippocampal neurogenesis in mice, and investigated how the activation of benzodiazepine receptors with diazepam interacted with the effects of MK801 on the precursor cells in the adult dentate gyrus. Our findings were: (i) one single MK801 application increased precursor cell proliferation and adult neurogenesis but not gliogenesis 4 weeks later; (ii) the number of label-retaining precursor cells decreased after MK801 (with P = 0.06); (iii) the pro-neurogenic effect included increased cell cycle entry of precursor cells as well as completed cell divisions, except in type-2a cells; (iv) NMDA receptor blockade also increased the number of nestin-GFP-expressing cells expressing calretinin; (v) diazepam alone had a very similar effect on overall precursor cell proliferation to that of MK801 alone; and (vi) diazepam, when co-applied with MK801, abolished the suppression of divisions of type-2a cells induced by MK801 alone, suppressed the MK801-induced effect on proliferation of type-2b cells and had no influence on the effects of MK801 on type-3 cells, but did suppress the increased number of nestin-GFP-positive cells expressing calretinin. From these results we hypothesize that, depending on the precursor cell stage, NMDA-dependent neurotransmission has distinct effects that are partly antagonized and partly enhanced by GABAergic input. We propose that NMDA receptor-dependent signalling maintains the precursor cells in the dentate gyrus while blocking initial stages of development and promoting more advanced stages.