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Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice

Rampon, Claire, Tang, Ya-Ping, Goodhouse, Joe, Shimizu, Eiji, Kyin, Maureen, Tsien, Joe Z.·2000·Nature Neuroscience

DOI 10.1038/72945

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Abstract

We produced CA1-specific NMDA receptor 1 subunit-knockout (CA1-KO) mice to determine the NMDA receptor dependence of nonspatial memory formation and of experience-induced structural plasticity in the CA1 region. CA1-KO mice were profoundly impaired in object recognition, olfactory discrimination and contextual fear memories. Surprisingly, these deficits could be rescued by enriching experience. Using stereological electron microscopy, we found that enrichment induced an increase of the synapse density in the CA1 region in knockouts as well as control littermates. Therefore, our data indicate that CA1 NMDA receptor activity is critical in hippocampus-dependent nonspatial memory, but is not essential for experience-induced synaptic structural changes.

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Background
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NMDA receptor regulation of memory and behavior in humans
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“A line of genetic evidence further establishes the required role of CA1 NMDA receptors in certain types of learning (Tsien et al., 1996; McHugh et al., 1996; Rampon et al., 2000; Huerta et al., 2000).”
Background
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Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor α1 can be ameliorated by T3 treatmentPreprint
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“Moreover, a similar deficit was found in mice with a region-specific knockout of NMDA receptor 1 subunits in the CA1 (Rampon et al. 2000), while transgenic mice with forebrain NMDA receptor 2B subunit overexpression exhibit enhanced object recognition memory (Tang et al. 1999).”
Background
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Method
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Background
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Background
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Self-citation
Genome-wide gene expression profiles of the developing mouse hippocampus
Mody, M., Cao, Y., Cui, Z., Tay, K.-Y., Shyong, A., Shimizu, E., Pham, K., Schultz, P., Welsh, D., & Tsien, J. Z. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141244998 · Cited by 205
Self-citation
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Wang, H., Hu, Y., & Tsien, J. Z. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.06.004 · Cited by 214
Self-citation
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“Since an enriched environment has an impact on neuronal plasticity as well as on learning performance (Rampon et al. 2000), changes in the number or shape of dendritic spines could represent a morphological correlate of neuronal plasticity,”
Background
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Soderling, S. H., Langeberg, L. K., Soderling, J. A., Davee, S. M., Simerly, R., Raber, J., & Scott, J. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0438033100 · Cited by 202
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“The genetic inactivation of the critical NR1 subunit of the NMDA-receptor selectively in pyramidal cells of the CA1 region impaired one-trial object recognition in mice at delays ranging from 30min to 24 h (Rampon et al., 2000).”
Background
Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice
BENNETT, J., McRae, P. A., Levy, L. J., & Frick, K. M. (2005) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.09.003 · Cited by 210
“Still others did not house rodents with enriching stimuli, but exposed them to enrichment for 3 h/day (Frick & Fernandez, 2003; Rampon et al., 2000).”
Background
Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment
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“…been observed in response to EE, such as enhanced dendritic branching (Greenough and Volkmar, 1973; Bruel-Jungerman et al., 2005) synaptic density (Rampon et al., 2000), and neurogenesis (Paylor et al., 1992; Kempermann and Gage, 1998; Auvergne et al., 2002; Bruel-Jungerman et al., 2005) (for…”
Background
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“Additionally, genetically altered mice with hippocampal dysfunction also exhibit anterograde amnesia for the food preference task (Mayeux-Portas et al., 2000; Rampon et al., 2000).”
Background
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“Tukey–Kramer post-hoc analysis revealed that the effect was most pronounced in area CA1 where, under standard housing conditions, the offspring of low-LG mothers showed reduced expression of GluR3 mRNA compared with ª 2004 Federation of European Neuroscience Societies, European Journal of Neuroscience, 20, 1355–1362 t…”
BackgroundInfluential
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“…enrichment has been used to reverse cognitive deficits that result from prenatal stress (Koo et al., 2003), postnatal lead exposure (Guilarte et al., 2003), social isolation (Lu et al., 2003), and geneknockout models of cognitive disease (e.g. Fragile X; Rampon et al., 2000; Restivo et al., 2005).”
BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment
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“…al., 2006), enhanced learning and memory (Rampon et al., 2000b; Tang et al., 2001; Lee et al., 2003), improved functional recovery after ischemia (Dahlqvist et al., 1999) and recovery of memory deficits associated with disruption of N-methyl-D-aspartate receptors (NMDAR) (Ram- pon et al., 2000b).”
BackgroundInfluential

Authors: Rampon, C., Tang, Y.-P., Goodhouse, J., Shimizu, E., Kyin, M., & Tsien, J. Z.
Affiliations: Princeton University (US)
Corresponding author: Tsien, Joe Z.
ORCID: Rampon, Claire
Tang, Ya-Ping
Shimizu, Eiji
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2000-03-01
Volume: 3
Issue: 3
Pages: 238-244
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/72945
OpenAlex: W1481984979
Semantic Scholar: fa40536e2cbc3bd383f248197b5f4cb17804cd65
Cited by: 755
References: 41
Citations by year: 2026: 3 · 2025: 8 · 2024: 9 · 2023: 20 · 2022: 12 · 2021: 16 · 2020: 20 · 2019: 20 · 2018: 22 · 2017: 22 · 2016: 32 · 2015: 30 · 2014: 33 · 2013: 40 · 2012: 44
FWCI: 15.59
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: Foundation for the National Institutes of Health
Arnold and Mabel Beckman Foundation
Princeton University
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: NMDA receptor 1, CA1, hippocampus, memory impairment, object recognition memory, odor discrimination, contextual fear memory, environmental enrichment, synaptic plasticity, synaptic density, knockout mice, memory recovery
MeSH terms: Animals, Conditioning, Psychological, Cues, Dendrites, Electroshock, Exploratory Behavior, Fear, Female, Food Preferences, Male, Memory, Memory Disorders, Pattern Recognition, Visual, Smell, Space Perception, Synapses, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Pyramidal Cells, Mice, Knockout, Mice

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Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice

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