Delay-dependent impairment of spatial working memory with inhibition of NR2B-containing NMDA receptors in hippocampal CA1 region of rats

Zhang, Xue-Han; Liu, Shu-Su; Feng, Yi; Zhuo, Min; Li, Baoming

doi:10.1186/1756-6606-6-13

Cited by 56 publications

(44 citation statements)

References 36 publications

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“…Lack of PDYN gene expression prevented age-related AMPA GluR1 protein decrease and enhanced the NMDA NR2B level in the hippocampal formation of old mice, suggesting an important role of dynorphin signaling in the control of AMPA and NMDA receptor expression. Both subunits are closely linked with cognition and performances in spatial memory tasks [20,21,22,23], a form of cognition specifically altered in human and AD mouse models [24,25]. In line with our results, age-related cognitive deficits in the hippocampus-dependent Morris Water Maze spatial task are reduced in Pdyn KO mice [26].…”

Section: Discussionsupporting

confidence: 84%

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

et al. 2013

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Background/Aims: Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD. Methods: Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice. Results: We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals. Conclusions: These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.

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Section: Discussionsupporting

confidence: 84%

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

et al. 2013

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“…Inter alia, NR2B-containing NMDA receptors are the most important for the regulation of intracellular signaling pathways coupled to ERK1/2 (Paul and Connor, 2010). They are pivotal modulators of synaptic plasticity (Astori and Luthi, 2013;Dupuis et al, 2014) as well as learning and memory functions (Brim et al, 2013;Vedder et al, 2013;Zhang et al, 2013) and their persistent activation can trigger excitotoxic processes Liu and Zhao, 2013;Stanika et al, 2009;Vizi et al, 2013;Zhang et al, 2013). Hence, NR2B-containing NMDAR are crucially involved in the fine tuning of the functional properties and resilience of neurons.…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure

Navarria¹,

Zaltieri²,

Longhena³

et al. 2015

Neurochemistry International

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“…Inactivation of or lesions to the CA1 region of the hippocampus produces severe deficits in delay dependent spatial working memory [5]. NMDAR antagonists also produce dose dependent memory deficits [5-8]. These results underscore the adverse pharmacological effects associated with global NMDAR antagonists, consistent with the broad role of NMDAR signaling in cell physiology and function.…”

Section: Introductionmentioning

confidence: 97%

“…The NMDAR signaling complex is implicated in learning and memory consistent with the presence of NMDARs in the hippocampus, a brain structure essential for memory. Inactivation of or lesions to the CA1 region of the hippocampus produces severe deficits in delay dependent spatial working memory [5]. NMDAR antagonists also produce dose dependent memory deficits [5-8].…”

Section: Introductionmentioning

confidence: 99%

Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein–protein interaction inhibitors

Smith

Lai

et al. 2016

Behavioural Brain Research

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Limitations of preclinical models of human memory contribute to the pervasive view that rodent models do not adequately predict therapeutic efficacy in producing cognitive impairments or improvements in humans. We used a source-memory model (i.e. a representation of the origin of information) we developed for use in rats to evaluate possible drug-induced impairments of both spatial memory and higher order memory functions in the same task. Memory impairment represents a major barrier to use of NMDAR antagonists as pharmacotherapies. The scaffolding protein postsynaptic density 95kDa (PSD95) links NMDARs to the neuronal enzyme nitric oxide synthase (nNOS), which catalyzes production of the signaling molecule nitric oxide (NO). Therefore, interrupting PSD95-nNOS protein-protein interactions downstream of NMDARs represents a novel therapeutic strategy to interrupt NMDAR-dependent NO signaling while bypassing unwanted side effects of NMDAR antagonists. We hypothesized that the NMDAR antagonist MK-801 would impair source memory. We also hypothesized that PSD95-nNOS inhibitors (IC87201 and ZL006) would lack the profile of cognitive impairment associated with global NMDAR antagonists. IC87201 and ZL006 suppressed NMDA-stimulated formation of cGMP, a marker of NO production, in cultured hippocampal neurons. MK-801, at doses that did not impair motor function, impaired source memory under conditions in which spatial memory was spared. Thus, source memory was more vulnerable than spatial memory to impairment. By contrast, PSD95-nNOS inhibitors, IC87201 and ZL006, administered at doses that are behaviorally effective in rats, spared source memory, spatial memory, and motor function. Thus, PSD95-nNOS inhibitors are likely to exhibit favorable therapeutic ratios compared to NMDAR antagonists.

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Delay-dependent impairment of spatial working memory with inhibition of NR2B-containing NMDA receptors in hippocampal CA1 region of rats

Cited by 56 publications

References 36 publications

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure

Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein–protein interaction inhibitors

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