Differential effects of enrichment on learning and memory function in NR2B transgenic mice

Tang, Ya Ping; Wang, H; Feng, Ru; Kyin, Maureen; Tsien, Joseph Zhuo

doi:10.1016/s0028-3908(01)00122-8

Cited by 298 publications

(206 citation statements)

References 51 publications

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“…In all age groups, enrichment attenuated contextual freezing. Even if this result is inconsistent with previous studies showing that enrichment tended to increase contextual fear (Briand et al 2005;Duffy et al 2001;Tang et al 2001), we previously showed (Barbelivien et al 2006) that if, in adult rats, enrichment increased fear to a background context (i.e., when a tone perfectly predicts footshock occurrence), it concomitantly decreased fear to a foreground context (i.e., no predictive tone), as found in the current study at all ages. Therefore, the lower freezing scores that we observed in enriched rats may reflect a genuine decrease in fear rather than a deficit in contextual conditioning.…”

Section: Emotional Behaviorscontrasting

confidence: 99%

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

Harati

Barbelivien

Herbeaux

et al. 2012

AGE

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We assessed lifelong environmental enrichment effects on possible age-related modifications in emotional behaviors, spatial memory acquisition, retrieval of recent and remote spatial memory, and cholinergic forebrain systems. At the age of 1 month, Long-Evans female rats were placed in standard or enriched rearing conditions and tested after 3 (young), 12 (middle-aged), or 24 (aged)months. Environmental enrichment decreased the reactivity to stressful situations regardless of age. In the water maze test, it delayed the onset of learning deficits and prevented age-dependent spatial learning and recent memory retrieval alterations. Remote memory retrieval, which was altered independently of age under standard rearing conditions, was rescued by enrichment in young and middle-aged, but unfortunately not aged rats. A protected basal forebrain cholinergic system, which could well be one out of several neuronal manifestations of lifelong environmental enrichment, might have contributed to the behavioral benefits of this enrichment.

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Section: Emotional Behaviorscontrasting

confidence: 99%

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

Harati

Barbelivien

Herbeaux

et al. 2012

AGE

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“…To date, EE has been shown to upregulate the expression of other NMDAR subunits and additional components of the glutamatergic system, signifying that restoration of NMDAR dysfunction either directly through NMDARs or through enhancing glutamatergic signaling may be a critical component in the beneficial effects of EE on behavior (Tang et al, 2001;Bredy et al, 2003;Naka et al, 2005;Andin et al, 2007;Mora et al, 2007;Sun et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, this form of environmental modification has been demonstrated to ameliorate behavioral abnormalities in rodent models of psychiatric disorders, including schizophrenia-like behaviors (Brenes et al, 2008;Chourbaji et al, 2008;McOmish et al, 2008). EE has been shown to upregulate expression of NMDAR subunits, as well as other components of the glutamatergic system (Tang et al, 2001;Bredy et al, 2003;Naka et al, 2005;Andin et al, 2007;Mora et al, 2007) suggesting that disruptions resulting from NMDAR dysfunction could be ameliorated following exposure to enriched housing. However, it is not clear whether EE influences the behavioral consequences of mGlu5 deficiency and what the role of NMDAR in these changes is.…”

Section: Introductionmentioning

confidence: 99%

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Burrows

McOmish

Buret

et al. 2015

Neuropsychopharmacol

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Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophreniarelated behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

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“…81 Both mutants show persistent hyperactivity and stereotypic behaviors that are resistant to reversal with either antipsychotics or benzodiazepines, indicating that dysfunction of the glycine-site itself is sufficient to cause schizophrenia-like behavioral abnormalities. In contrast to knockdown mice, NR1 overexpressing mice show increased learning ability, 82 as do mice with partial GLYT1 receptor knockouts, 83 emphasizing the potential importance of NMDAR dysfunction to cognitive impairments in schizophrenia.…”

Section: Animal Modelsmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Differential effects of enrichment on learning and memory function in NR2B transgenic mice

Cited by 298 publications

References 51 publications

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Glutamate as a therapeutic target in psychiatric disorders

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