Abstract
Adult neurogenesis in the dentate gyrus plays a critical role in hippocampus-dependent spatial learning. It remains unknown, however, how new neurons become functionally integrated into spatial circuits and contribute to hippocampus-mediated forms of learning and memory. To investigate these issues, we used a mouse model in which the differentiation of adult-generated dentate gyrus neurons can be anticipated by conditionally expressing the pro-differentiative gene PC3 (Tis21/BTG2) in nestin-positive progenitor cells. In contrast to previous studies that affected the number of newly generated neurons, this strategy selectively changes their timing of differentiation. New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density. Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, 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 defined 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, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.
Highlights
Observations in mammals and birds have revealed that neurogenesis continues in the dentate gyrus of the hippocampus throughout adulthood, due to the presence of progenitor cells localized in the innermost part of the granule cell layer, the subgranular zone (SGZ, [1,2,3])
We have developed a different approach, using a mouse model that accelerates the differentiation of the newly generated neurons without altering their number, and offers the possibility to induce the process at any chosen moment
We show that the new neurons pass through their early stages of maturation faster and, though establishing connections with the existing neuronal circuits, fail to function properly
Summary
Observations in mammals and birds have revealed that neurogenesis continues in the dentate gyrus of the hippocampus throughout adulthood, due to the presence of progenitor cells localized in the innermost part of the granule cell layer, the subgranular zone (SGZ, [1,2,3]) These progenitor cells continue to proliferate and generate new dentate granule neurons for the entire life of the organism [4,5]. The process of adult hippocampal neurogenesis originates from dividing putative neural stem cells [6] and has been tentatively divided into six developmental stages [7], in which putative neural stem cells (named type-1 cells) develop into post-mitotic neurons through three consecutive stages of progenitor cells (type-2ab and type-3 cells; [8,9,10]). Recent observations indicate that new neurons of the dentate gyrus become functionally active in learning circuits at late stages of their maturation (;4–6 postnatal weeks, [21])
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