The Timing of Differentiation of Adult Hippocampal Neurons Is Crucial for Spatial Memory

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. Previous studies have implicated adult-born hippocampal neurons in the formation of spatial and contextual memories by using mouse models where newly generated neurons are either eliminated or increased in number. Nonetheless, how new neurons are integrated in the existing circuits and contribute to memory formation still awaits clarification. Toward this end, 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. In fact, mice are not only unable to learn new spatial information, but they are also unable to use previously acquired memories. These results demonstrate that the appropriate timing of maturation of new neurons is important for their adult performance in memory circuits, i.e., to integrate new memory traces and recall previous events.