Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 19, 2018 (received for review June 14, 2018)
Spatial learning and memory are hippocampal functions that emerge and mature during early postnatal development. The molecular mechanisms which shape this process are largely unknown. Here, we present evidence that the activity-regulated gene Arc/Arg3.1 is transiently up-regulated in the hippocampus of neonatal mice where it is required for establishing appropriate hippocampal network activity essential for spatial learning. Once established, network activity supports normal spatial learning in the absence of Arc/Arg3.1 while long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that hippocampal networks undergo a critical period of development mediated by Arc/Arg3.1 and open opportunities to investigate normal and pathological neurodevelopment of higher brain functions.
During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up-regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage.
↵1X.G., S.C.-G., and J.G. contributed equally to this work.
↵2Present address: Department of Neurodegenerative Diseases & Geropsychiatry, University Hospital Bonn, 53127 Bonn, Germany.
Author contributions: D.K. and O.O. designed research; X.G., S.C.-G., J.G., S.G., U.S., L.B., D.M., and D.I. performed research; X.G., S.C.-G., J.G., D.I., D.K., and O.O. analyzed data; and X.G., S.C.-G., J.G., D.K., and O.O. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1810125115/-/DCSupplemental.
Published under the PNAS license.
