The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory

Tsien, Joe Z.; Huerta, Patricio T.; Tonegawa, Susumu

doi:10.1016/s0092-8674(00)81827-9

Cited by 1,597 publications

(1,231 citation statements)

References 50 publications

(16 reference statements)

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“…Perhaps the repeated elevation of dopamine, which remains intact in NR1-KD mice, can eventually induce equivalent neurochemical changes that cocaine normally elicits through the combination of NMDA receptor and dopamine receptor neurotransmission. An alternative explanation for the delayed performance in the CPP paradigm may be that these mice have difficulties associating environmental cues with the drug, as their spatial memory could be impaired due to decreased number of hippocampal NMDA receptors (Tsien et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Ramsey

Laakso

Cyr

et al. 2008

Neuropsychopharmacol

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NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre-and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Ramsey

Laakso

Cyr

et al. 2008

Neuropsychopharmacol

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“…Further evidence of NMDAR dysfunction in mGlu5 KO mice has been suggested by the loss of NMDAR-mediated components of hippocampal CA1 LTP (Lu et al, 1997;Jia et al, 1998). Accordingly, mGlu5 KO mice show memory impairments (Lu et al, 1997;Rodrigues et al, 2002;Gray et al, 2009) that depend on NMDAR-mediated plasticity in the CA1 region of the hippocampus (Tsien et al, 1996). Allosteric modulators of mGlu5 have been developed with a view to target this receptor, therapeutically; however, the exact role of mGlu5 in schizophrenia endophenotypes remains unclear.…”

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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“…This result could not be ascribed to direct effects on the neocortex, however, as it could have been a consequence of impaired patterns at the brainstem level 6,12,13 . To delineate the specific role(s) of cortical NMDARs in patterning, here we disrupted the function of NR1-the essential subunit of the NMDAR-specifically in the cortex, using the Cre/loxP system 14 .…”

mentioning

confidence: 99%

“…We crossed the Emx1 Cre/Cre mice with heterozygous NR1 null mutant (NR1 +/− ) mice 12 to obtain double heterozygous (Emx1 Cre/+ NR1 +/− ) mice, and further crossed these with homozygous floxed NR1 (NR1 flox/flox ) mice 14 to obtain four types of mice: Emx1 Cre/+ NR1 flox/− ; Emx1 +/+ NR1 flox/− ; Emx1 Cre/+ NR1 flox/+ ; and Emx1 +/+ NR1 flox/+ . Emx1 Cre/+ NR1 flox/− mice constitute cortex-specific NR1 knockout mice, and hereafter we refer to them as CxNR1KO mice.…”

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confidence: 99%

Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex

Iwasato

Datwani

Wolf

et al. 2000

Nature

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In the rodent primary somatosensory cortex, the configuration of whiskers and sinus hairs on the snout and of receptor-dense zones on the paws is topographically represented as discrete modules of layer IV granule cells (barrels) and thalamocortical afferent terminals 1,2 . The role of neural activity, particularly activity mediated by NMDARs (N-methyl-D-aspartate receptors), in patterning of the somatosensory cortex has been a subject of debate [3][4][5][6] . We have generated mice in which deletion of the NMDAR1 (NR1) gene is restricted to excitatory cortical neurons, and here we show that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocortical afferents corresponding to large whiskers form patterns and display critical period plasticity, but their patterning is not as distinct as that seen in the cortex of normal mice. Other thalamocortical patterns corresponding to sinus hairs and digits are mostly absent. The cellular aggregates known as barrels and barrel boundaries do not develop even at sites where thalamocortical afferents cluster. Our findings indicate that cortical NMDARs are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns.The rodent somatosensory system is an excellent model to study molecular mechanisms underlying the establishment of patterned topographic connections between the sensory periphery and the brain. Trigeminal and dorsal column pathways convey a somatosensory map from the periphery to the neocortex by relay stations in the brainstem and the ventrobasal thalamus. At each level, pre-synaptic afferents and their target cells establish a patterned array of modules corresponding to the arrangement of whiskers and sinus hairs on the snout (trigeminal pathway), and receptor-dense zones of the paws (dorsal column pathway) 2,7,8 . These patterns are consolidated during the first postnatal week, and are subject to alterations if the sensory periphery is perturbed by nerve or whisker lesions during a critical period 2,7,8 . Thus, early neural activity might be essential in the development and plasticity of central patterns much like that of the vertebrate visual system 9,10 . Within this context, NMDAR activity has attracted much attention 9,11 . Initial studies using pharmacological blockade of NMDARs in postnatal rat somatosensory cortex did not detect effects on thalamocortical patterning, but revealed functional impairment of thalamocortical connectivity and whisker-specific responsiveness of barrel neurons 4,5 . In contrast, genetic manipulations of NMDARs showed an absence of periphery-related patterns in the somatosensory cortex 6 . This result could not be ascribed to direct effects on the neocortex, however, as it could have been a consequence of impaired patterns at the brainstem level 6,12,13 . To delineate the specific role(s) of cortical NMDARs in patterning, here we disrupted the ...

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The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory

Cited by 1,597 publications

References 50 publications

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

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

Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex

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