Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice
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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Mice with selective NMDA-R subunit 1 knockout in the hippocampal CA1 area exhibited NOP deficits.
“mice with selective NMDA-R subunit 1 knockout in the hippocampal CA1 area exhibited NOP deficits”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Rampon et al., 2000
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“More recent data from microarray studies have shown that EE housing induces expression of gene cascades involved with NMDAdependent plasticity and neuroprotection (Rampon et al, 2000).”
BackgroundResultInfluentialDifferential effects of enrichment on learning and memory function in NR2B transgenic mice
Tang, Y., Wang, H., Feng, R., Kyin, M., & Tsien, J. Z. (2001) · Neuropharmacology · doi:10.1016/s0028-3908(01)00122-8 · Cited by 330 · see citing works
Self-citationThe effects of aging on gene expression in the hypothalamus and cortex of mice
Jiang, C. H., Tsien, J. Z., Schultz, P. G., & Hu, Y. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1930 · Cited by 318 · see citing works
Self-citationThe nature and course of neuropsychological morbidity in chronic temporal lobe epilepsy
Oyegbile, T. O., Dow, C., Jones, J. E., Bell, B. D., Rutecki, P. A., Sheth, R. D., Seidenberg, M., & Hermann, B. P. (2004) · Neurology · doi:10.1212/01.wnl.0000125186.04867.34 · Cited by 323 · see citing works
Nithianantharajah, J., & Hannan, A. J. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.10.001 · Cited by 324 · see citing works
“One of the earliest molecular changes found to be induced by EE in the cerebral cortex is the altered transcription of immediate early genes (IEGs) (Rampon et al., 2000a).”
Experience-Dependent Epigenetic Modifications in the Central Nervous System
Sweatt, J. D. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.09.002 · Cited by 302 · see citing works
Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice
Frick, K. M., & Fernandez, S. M. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00138-0 · Cited by 303 · see citing works
“For example, enrichment can completely protect against learning and memory deficits in adult mice with a conditional knockout of the NMDAR1 receptor subunit in the hippocampal CA1 region [61].”
The Hippocampus Plays a Selective Role in the Retrieval of Detailed Contextual Memories
Wiltgen, B. J., Zhou, M., Cai, Y., Balaji, J., Karlsson, M. G., Parivash, S. N., Li, W., & Silva, A. J. (2010) · Current Biology · doi:10.1016/j.cub.2010.06.068 · Cited by 300 · see citing works
Schneider, T., Turczak, J., & Przewłocki, R. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300767 · Cited by 298 · see citing works
“…and branching in the cerebral cortex (eg Volkmar and Greenough, 1972; Diamond et al, 1964; Diamond, 1967; Greenough et al, 1973), hippocampus (Rampon et al, 2000), striatum (Comery et al, 1995), and cerebellum (Floeter and Greenough, 1979); reduced apoptosis (Young et al, 1999); increased…”
BackgroundYoung, J. W., Powell, S. B., Risbrough, V. B., Marston, H. M., & Geyer, M. A. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.02.004 · Cited by 299 · see citing works
Effects of Stress and Hippocampal NMDA Receptor Antagonism on Recognition Memory in RatsPreprint
Baker, K. B., & Kim, J. J. (2002) · Learning & Memory · doi:10.1101/lm.46102 · Cited by 292 · see citing works
Adult Hippocampal Neurogenesis, Synaptic Plasticity and Memory: Facts and Hypotheses
Bruel‐Jungerman, E., Rampon, C., & Laroche, S. (2007) · Reviews in the Neurosciences · doi:10.1515/revneuro.2007.18.2.93 · Cited by 281 · see citing works
Self-citationA hitchhiker's guide to behavioral analysis in laboratory rodents
Sousa, N., Almeida, O. F. X., & Wotjak, C. T. (2006) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2006.00228.x · Cited by 273 · see citing works
“…ensemble (nature) but also by environmental factors (nurture), e.g. pre- and postnatal maternal influences (Francis et al. 2003; Zaharia et al. 1996; for review, see Meaney 2001), phases of food restriction (Cabib et al. 2000) or enriched housing conditions (Feng et al. 2001; Rampon et al. 2000).”
BackgroundEnvironmental enrichment and the brain
Mohammed, A. H., Zhu, S., Darmopil, S., Hjerling‐Leffler, J., Ernfors, P., Winblad, B. G., Diamond, M. C., Eriksson, P. S., & Bogdanović, N. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)38074-9 · Cited by 267 · see citing works
“Deficits in mutant mice with selective lesions of NMDA receptors in the CA1 hippocampal region could also be reversed by raising the mutant mice in an enriched environment (Rampon et al., 2000b).”
Epigenetic Regulation of Neural Gene Expression and Neuronal Function
Feng, J., Fouse, S. D., & Fan, G. (2007) · Pediatric Research · doi:10.1203/pdr.0b013e3180457635 · Cited by 263 · see citing works
“Dnmt1 deficiency in neural precursor cells causes global demethylation in the entire CNS and neonatal death due to respiratory failure (24), consistent with a critical role for DNA methylation in controlling vital CNS functions.”
BackgroundBekinschtein, P., Oomen, C. A., Saksida, L. M., & Bussey, T. J. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.07.002 · Cited by 256 · see citing works
Macrı̀, S., & Würbel, H. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.015 · Cited by 253 · see citing works
“Thus, memory deficits induced by a conditional knock out of NMDA R1 receptors in the hippocampus were rescued by environmental enrichment through enhanced NMDA-independent neural connectivity in the hippocampus and neocortex (Rampon et al., 2000).”
BackgroundPhysical Exercise Protects Against Alzheimer's Disease in 3xTg-AD Mice
García‐Mesa, Y., López, J. C., Giménez‐Llort, L., Revilla, S., Guerra, R., Gruart, A., LaFerla, F. M., Cristòfol, R. M., Delgado-Garcia, J. M., & Sanfeliu, C. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101635 · Cited by 253 · see citing works
“The novel-object recognition assays which evaluate hippocampal-dependent nonspatial learning and memory [59] cannot be used because test-linked deficiences appear at advanced pathological stages in 3xTg-AD mice [26].”
BackgroundPrevention and treatment of drug addiction by environmental enrichment
Solinas, M., Thiriet, N., Chauvet, C., & Jaber, M. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.08.002 · Cited by 256 · see citing works
Artola, A., von Frijtag, J. C., Fermont, P. C. J., Gispen, W. H., Schrama, L. H., Kamal, A., & Spruijt, B. M. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04552.x · Cited by 253 · see citing works
Bredy, T. W., Humpartzoomian, R., Cain, D. P., & Meaney, M. J. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00918-1 · Cited by 248 · see citing works
Exploring the Validity of Valproic Acid Animal Model of Autism
Mabunga, D. F. N., Gonzales, E. L., Kim, J., Kim, K. C., & Shin, C. Y. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.4.285 · Cited by 247 · see citing works
“Evidence of environmental enrichment enhancing the performance of rats in various learning tasks [98, 99] and social behavior [100] has led to the hypothesis that it can also be beneficial to brain-damaged animals [101].”
BackgroundWang, X., Zhao, Y., Zhang, X., Badie-Mahdavi, H., Zhou, Y., Mu, Y., Loo, L. S., Cai, L., Thompson, R. C., Yang, B., et al. (2013) · Nature Medicine · doi:10.1038/nm.3117 · Cited by 241 · see citing works
NMDA receptor regulation of memory and behavior in humans
Newcomer, J. W., & Krystal, J. (2001) · Hippocampus · doi:10.1002/hipo.1069 · Cited by 258 · see citing works
“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).”
BackgroundHalperin, J. M., & Healey, D. M. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.07.006 · Cited by 237 · see citing works
Dewachter, I., Reversé, D., Caluwaerts, N., Ris, L., Kuipéri, C., den Haute, C. V., Spittaels, K., Umans, L., Serneels, L., Thiry, E., et al. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03445.2002 · Cited by 236 · see citing works
“The object recognition task was essentially performed as described (Tang et al., 1999; Rampon et al., 2000).”
MethodMolecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Weickert, C. S., Fung, S. J., Catts, V. S., Schofield, P. R., Allen, K. M., Moore, L., Newell, K. A., Pellen, D., Huang, X.-F., Catts, S. V., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.137 · Cited by 234 · see citing works
Behaviour and the standardization fallacy
Würbel, H. (2000) · Nature Genetics · doi:10.1038/81541 · Cited by 235 · see citing works
On whether the environmental enrichment may provide cognitive and brain reserves
Petrosini, L., Bartolo, P. D., Foti, F., Gelfo, F., Cutuli, D., Leggio, M. G., & Mandolesi, L. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.07.002 · Cited by 233 · see citing works
Plasticity, Robustness, Development and Evolution
(2012) · International Journal of Epidemiology · doi:10.1093/ije/dys033 · Cited by 223 · see citing works
Different modes of hippocampal plasticity in response to estrogen in young and aged female rats
Adams, M. M., Shah, R. A., Janssen, W. G. M., & Morrison, J. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141215898 · Cited by 222 · see citing works
Venero, C., Guadaño‐Ferraz, A., Herrero, A. I., Nordström, K., Manzano, J., de Escobar, G. M., Bernal, J., & Vennström, B. (2005) · Genes & Development · doi:10.1101/gad.346105 · Cited by 222 · see citing works
“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).”
BackgroundAberrant responses in social interaction of dopamine transporter knockout mice
Rodriguiz, R. M., Chu, R., Caron, M. G., & Wetsel, W. C. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00187-6 · Cited by 221 · see citing works
Ricobaraza, A., Cuadrado‐Tejedor, M., Marco, S., Pérez‐Otaño, I., & García‐Osta, A. (2012) · Hippocampus · doi:10.1002/hipo.20883 · Cited by 239 · see citing works
“The CA1 region was chosen for spine analysis because it has been shown to be critical for contextual fear conditioning (Rampon et al., 2000).”
Methodde Lima, M. N. M., Laranja, D. C., Bromberg, E., Roesler, R., & Schröder, N. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.05.016 · Cited by 215 · see citing works
Haettig, J., Stefanko, D. P., Multani, M. L., Figueroa, D. X., McQuown, S. C., & Wood, M. A. (2011) · Learning & Memory · doi:10.1101/lm.1986911 · Cited by 211 · see citing works
“Many studies have found that hippocampal damage impairs memory (Clark et al. 2000; Rampon et al. 2000; Baker and Kim 2002; Gould et al. 2002; Gaskin et al. 2003; Broadbent et al. 2004; Hammond et al. 2004; Prusky et al. 2004; Ainge et al. 2006; de Lima et al. 2006; Rossato et al. 2007), whereas…”
BackgroundA Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment
Faherty, C. J., Kerley, D. A., & Smeyne, R. J. (2003) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00642-9 · Cited by 210 · see citing works
Bézard, E., Doveró, S., Belin, D., Duconger, S., Jackson-Lewis, V. R., Przedborski, S., Piazza, P. V., Gross, C. E., & Jaber, M. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-35-10999.2003 · Cited by 209 · see citing works
“Indeed, they show that life conditions can compensate for behavioral impairments provoked by two genetic mutations, one inducing motor disturbances mimicking Huntington’s disease (Van Dellen et al., 2000) and the other a marked memory impairment (Rampon et al., 2000).”
BackgroundFrick, K. M. (2009) · Hormones and Behavior · doi:10.1016/j.yhbeh.2008.08.015 · Cited by 205 · see citing works
“…memory and enhances hippocampal morphology and plasticity in young-adult (Davis et al., 2004; Duffy et al., 2001; Kempermann et al., 1997; Rampon et al., 2000), middle-aged (Frick et al., 2003; Kempermann et al., 1998), and aged (Frick et al., 2002b; Nakamura et al., 1999; Soffié et al.,…”
BackgroundLinking Hebb's coincidence-detection to memory formation
Tsien, J. Z. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00070-2 · Cited by 205 · see citing works
Self-citationGenome-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 · see citing works
Self-citationMolecular and systems mechanisms of memory consolidation and storage
Wang, H., Hu, Y., & Tsien, J. Z. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.06.004 · Cited by 205 · see citing works
Self-citationBDNF effects on dendritic spine morphology and hippocampal function
von Bohlen und Halbach, O., & von Bohlen und Halbach, V. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2782-x · Cited by 218 · see citing works
“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,”
BackgroundLoss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice
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 · see citing works
The case for episodic memory in animals
Dere, E., KARTTEKE, E., Huston, J. P., & DESOUZASILVA, M. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.09.005 · Cited by 202 · see citing works
“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).”
BackgroundBENNETT, 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 198 · see citing works
“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).”
BackgroundArai, J. A., Li, S., Hartley, D. M., & Feig, L. A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5057-08.2009 · Cited by 195 · see citing works
“…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…”
BackgroundClark, R. E., Broadbent, N., Zola, S. M., & Squire, L. R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-11-04663.2002 · Cited by 196 · see citing works
“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).”
BackgroundBredy, T. W., Zhang, T. Y., Grant, R. J., Diorio, J., & Meaney, M. J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03599.x · Cited by 196 · see citing works
“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…”
BackgroundInfluentialSocial influences on neurobiology and behavior: Epigenetic effects during development
Curley, J. P., Jensen, C. L., Rahia Mashoodh, A., & Champagne, F. A. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.06.005 · Cited by 195 · see citing works
“…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).”
Novkovic, T., Mittmann, T., & Manahan‐Vaughan, D. (2014) · Hippocampus · doi:10.1002/hipo.22342 · Cited by 189 · see citing works
“…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.
- Venue
- Nature Neuroscience
- Published
- 2000-03-01
- Volume
- 3
- Issue
- 3
- Pages
- 238-244
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1481984979
- Semantic Scholar
- fa40536e2cbc3bd383f248197b5f4cb17804cd65
- Cited by
- 737
- References
- 41
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 11 · 2023: 21 · 2022: 7 · 2021: 15 · 2020: 19 · 2019: 20 · 2018: 22 · 2017: 22 · 2016: 28 · 2015: 28 · 2014: 32 · 2013: 40 · 2012: 40
- FWCI
- 17.24
- Type
- journal article
- Language
- en
- Open access
- closed
- 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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