Long-term potentiation enhances neurogenesis in the adult dentate gyrus

Abstract

Activity-dependent synaptic plasticity and neurogenesis are two forms of brain plasticity that can participate in functional remodeling of neural networks during the formation of memories. We examined whether long-term potentiation (LTP) of excitatory synaptic transmission, a well characterized form of synaptic plasticity believed to play a critical role in memory formation, can regulate the rate of neurogenesis in the adult rat dentate gyrus in vivo. We first show that induction of LTP at medial perforant path-granule cell synapses stimulates the proliferation of progenitor cells in the dentate gyrus with a consequential long-term persistence of a larger population of surviving newborn cells. Using protocols to examine the effect of LTP on survival, we next show that LTP induction promotes survival of 1- to 2-week-old dentate granule cells. In no case did LTP appear to affect neuronal differentiation. Finally, we show that LTP induces expression of the plasticity-related transcription factor Zif268 in a substantial fraction of 2-week-old but not 1-week-old neurons, suggesting the prosurvival effect of LTP can be observed in the absence of LTP-mediated Zif268 induction in newborn cells. Our results indicate that electrically induced LTP in the dentate gyrus in vivo provides a cellular/molecular environment that favors both proliferation and survival of adult-generated neurons.

Figure 1.

LTP enhances proliferation and later survival of newborn cells in vivo. a, Perforant path tetanus (bar) induced stable LTP of the fEPSP, whereas pseudotetanus (PT) had no effect. Evoked potentials recorded before and after LTP are shown above. b, Average total number of BrdU-labeled cells (mean ± SEM) in the DG from the control, LTP, and PT sides. LTP was induced 1 d or 4 d before BrdU injections and rats were killed 24 h (proliferation) or 4 weeks (survival) later. ∗p < 0.05; ∗∗p < 0.005. c, Representative images of sections (control and LTP sides) stained for BrdU (dark) with nuclear fast red counterstaining (pink) from an animal injected with BrdU 4 d after LTP induction and killed 24 h after. Insets, Illustrations of clusters. d, Confocal images of BrdU (red) and early neuronal marker Prox-1 (green) immunohistochemistry illustrating colocalization (merged) in DGCs (arrowheads). e, LTP induction 4 d before BrdU injections resulted in more BrdU-labeled cells at the 4 week survival time.

Figure 2.

LTP enhances survival of recently born DGCs. a, Time course of LTP of the fEPSP slope, as in Figure 1a. b, Average total number of BrdU-labeled cells (mean ± SEM) in the DG from control, and LTP or PT sides. LTP was induced 1 or 2 weeks after BrdU injections and rats were killed at the survival time of 4 weeks post-BrdU. ∗p < 0.05; ∗∗p < 0.01. c, Representative BrdU-stained sections (control and LTP sides, see Fig. 1b) at 4 week survival time from an animal in which LTP was induced 2 weeks after BrdU injections. d, Confocal images of double-stained cells for BrdU (red) and NeuN (green) 4 weeks after BrdU injections illustrating colocalization (merged) in DGCs (arrowheads). e, Confocal images of double-immunostaining for BrdU (red) and Zif268 (green) 2 h after LTP induction from an animal injected with BrdU 2 weeks before LTP induction.