These

results indicate that the axons of selleck screening library DGCs born at P15 are synaptically integrated by P23 to compete with mature axons. To examine the specificity of the effect of AraC, we used DG-S mice. In DG-S mice, tTA is expressed by mature DGCs (37.1% ± 1.4%; Figures 3B and 3C) and CA1 neurons (48.2% ± 3.3%; Figure S5). Using DG-S::TeTxLC-tau-lacZ mice, we addressed whether AraC specifically inhibits the elimination of inactive DG axons or also affects the elimination of inactive CA1 axons. If the effect of AraC is through the suppression of neurogenesis, the elimination of inactive CA1 axons should not be affected. In DG-S::TeTxLC-tau-lacZ mice, axons PD-332991 of TeTxLC-expressing DG and CA1 neurons were both eliminated between P15 and P25 (Figure 3F and Figure 8A). After P25, very few TeTxLC-expressing axons were observed in both regions. On the other hand, DG-S::tau-lacZ mice (no TeTxLC) maintained β-gal-expressing axons of DG and CA1 neurons at P25 (Figure 8C). Thus, in DG-S mice, DG and CA1 axons are refined in an activity-dependent

manner between P15 and P25. We administered AraC daily (i.p. injection) from P15 to P22 (8 days total) into DG-S::TeTxLC-tau-lacZ mice. AraC injections inhibited the elimination of TeTxLC-expressing DG axons, but not that of TeTxLC-expressing CA1 axons (Figure 8D). Therefore, the effect of AraC is specific to DG axons, which is consistent with the fact

that neurogenesis is specific to the DG in the hippocampus. Finally, using DG-S mice, we addressed whether the DG axon refinement is mainly achieved by competition between mature and young DG axons or also by competition between mature and mature axons. In DG-S mice, tTA is expressed only by 37.1% ± 1.4% of mature DGCs (Figures 3B and 3C). If competition between mature and mature neurons equally contributes to refinement, AraC injections should not inhibit inactive axon elimination in the DG-S::TeTxLC-tau-lacZ line, which contains both active and inactive mature DGCs. Interestingly, however, AraC injections (from P15 to P22) inhibited the elimination of TeTxLC-expressing DG axons in DG-S::TeTxLC-tau-lacZ mice (Figures second 8D and 8E) as effectively as in DG-A::TeTxLC-tau-lacZ mice (Figures 6D and 6E). This suggests that the activity-dependent competition of DG axons is largely between axons of mature and young neurons. To further confirm that young neurons drive inactive axon elimination in the DG, we utilized nestin-tk animals, in which herpes simplex virus thymidine kinase is expressed under the control of the nestin enhancer to drive expression in neural progenitors (Singer et al., 2009). In this animal, administration of ganciclovir efficiently and specifically kills neural progenitors.