Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Kochlamazashvili, Gaga; Bukalo, Olena; Senkov, Oleg; Salmen, Benedikt; Gerardy‐Schahn, Rita; Engel, Andreas K.; Schachner, Melitta; Dityatev, Alexander

doi:10.1523/jneurosci.5103-11.2012

Cited by 45 publications

(35 citation statements)

References 103 publications

(153 reference statements)

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“…Consistent with a role for GluN2A in the behavioral responses observed, MK-801 has been shown to have much higher affinity for GluN2A-containing NMDARs and thus, an increase in GluN2A-containing NMDARs could explain the increased sensitivity to MK-801 seen following EE (Laurie and Seeburg, 1994;Gielen et al, 2009). Furthermore, several lines of evidence support the essential role of GluN2A-containing receptors in LTP, thus it is feasible that in the present study, enrichment improved learning in mGlu5 KO mice by enhancing LTP (Kochlamazashvili et al, 2012;Volianskis et al, 2013). Further examination of functional properties of NMDAR in mGlu5 KO mice following enrichment is warranted to confirm this.…”

Section: Discussionsupporting

confidence: 51%

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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Section: Discussionsupporting

confidence: 51%

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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“…The addition of colominic acid/PSA or of soluble PSA-carrying NCAM to acute hippocampal slices of NCAM-deficient mice restores long term potentiation that is impaired in NCAM-deficient mice, whereas application to the hippocampus of wild-type mice leads to impairment in formation of hippocampus-dependent contextual memory (26). The addition of colominic acid/PSA increased the open time of the AMPA receptors (57,59), whereas colominic acid/PSA addition prevents activation of GluN2B-containing NMDA receptors at low glutamate concentrations (60).…”

Section: Discussionmentioning

confidence: 99%

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

Theis

Mishra

Ohe

et al. 2013

Journal of Biological Chemistry

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Background: Polysialic acid (PSA) plays important roles in the developing and adult nervous system. Results: The interaction of PSA with myristoylated alanine-rich C kinase substrate (MARCKS) at the plasma membrane regulates neurite outgrowth. Conclusion:The MARCKS/PSA interaction regulates PSA-triggered signal transduction. Significance: Study of the molecular mechanisms underlying PSA-induced cellular responses helps to understand the functions of PSA in the nervous system.

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“…Whereas constitutive NCAM knockout mice have been much characterized (Theodosis et al 2004;Tereshchenko et al 2011;Kochlamazashvili et al 2012), information regarding the (neuro)-physiological impact of the mutation in NCAMffcre mice is scarce. However, available information indicates an existing vulnerability in these mice.…”

Section: Discussionmentioning

confidence: 99%

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

et al. 2013

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Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However, whether aging is associated with NCAM alterations that might contribute to age-related cognitive decline is not currently known. In this study, we determined whether conditional NCAM-deficient mice display increased vulnerability to age-related cognitive and emotional alterations. We assessed the NCAM expression levels in the hippocampus and medial prefrontal cortex (mPFC) and characterized the performance of adult and aged conditional NCAM-deficient mice and their age-matched wild-type littermates in a delayed matching-to-place test in the Morris water maze and a delayed reinforced alternation test in the T-maze. Although aging in wild-type mice is associated with an isoform-specific reduction of NCAM expression levels in the hippocampus and mPFC, these mice exhibited only mild impairments in working/episodic-like memory performance. However, aged conditional NCAM-deficient mice displayed pronounced impairments in both the delayed matching-to-place and the delayed reinforced alternation tests. Importantly, the deficits of aged NCAM-deficient mice in these working/episodic-like memory tasks could not be attributed to increased anxiety-like behaviors or to differences in locomotor activity. Taken together, these data indicate that reduced NCAM expression in the forebrain might be a critical factor for the occurrence of cognitive impairments during aging.[Supplemental material is available for this article.]One of the hallmarks of normal aging is a gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in brain regions that play a key role in cognitive functions, such as the hippocampus and the prefrontal cortex (Seki and

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Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Cited by 45 publications

References 103 publications

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

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

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

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