In the dentate gyrus adult neurogenesis plays a critical role in hippocampus-dependent spatial learning. However, how new neurons become functionally integrated into spatial circuits and contribute to learning and memory remains yet unknown. To study this issue, we used a mouse model in which the differentiation of adultgenerated dentate gyrus neurons can be anticipated by conditionally expressing the pro-differentiative gene PC3 (Tis21/BTG2) in nestin-positive progenitor cells. This strategy selectively changes the timing of differentiation of newly generated neurons without affecting their number. New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation, reduced dendritic arborization and spine density. The genetic manipulation affected different hippocampusdependent learning and memory tasks and selectively reduced synaptic plasticity in the dentate gyrus. Morphological and functional analyses of hippocampal neurons at different stages of differentiation, following transgene activation within defi ned time-windows, revealed that the new, adult-generated neurons up to 3–4 weeks of age are required not only to acquire new spatial information but also to use previously consolidated memories. Thus, the correct unwinding of these key memory functions is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.
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