The timing of differentiation of adult hippocampal neurons is crucial for spatial memory.
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.
Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Fondazione S Lucia, Rome, Italy.
Stefano
S
Farioli-Vecchioli
Daniele
D
Saraulli
Marco
M
Costanzi
Simone
S
Pacioni
Irene
I
Cinà
Massimiliano
M
Aceti
Laura
L
Micheli
Alberto
A
Bacci
Vincenzo
V
Cestari
Felice
F
Tirone
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D013028:Space Perception / Q000502:physiology; D013997:Time Factors; D025521:Tumor Suppressor Proteins
C489435:Btg2 protein, mouse; D017874:Immediate-Early Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D025521:Tumor Suppressor Proteins