Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats

Sun, Yanyan; Cai, Wei; Yu, Jie; Liu, Shu-Su; Zhuo, Min; Li, Baoming; Zhang, Xue-Han

doi:10.1038/srep30743

Cited by 16 publications

(13 citation statements)

References 59 publications

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“…Blockade of GluN2B activity in vivo in adult rodents following the induction of LTP can block its decay (Sachser et al, 2016) suggesting that GluN2B plays a critical role in updating memory traces. Indeed, GluN2B antagonism in the CA1 has been shown to impair hippocampal-dependent learning and memory tasks such as object recognition (Sachser et al, 2016) and contextual fear conditioning (Sun et al, 2016). Further supporting its role in plasticity, genetic overexpression of GluN2B in the CA1 enhances LTP in adult and aged mice, as well as adult rats (Cao et al, 2007; Tang et al, 1999; Wang et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm

Kenton

Castillo

Holmes

et al. 2018

Neurobiology of Learning and Memory

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Discrimination of similar spatial locations, an important feature of episodic memory, has traditionally been measured via delayed nonmatching-to-location tasks. Recently, we and others have demonstrated that touchscreen-based Trial Unique Nonmatching-to-Location (TUNL) tasks are sensitive to lesions of the dorsal hippocampus in the mouse. Previously we have shown that loss of the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor in the dorsal CA1 and throughout the cortex impairs hippocampal-dependent water maze and fear conditioning paradigms. We investigated whether loss of GluN2B would alter performance of visual-spatial discrimination learning in a delay- or separation-dependent manner. GluN2B null mutants displayed initial impairments in accuracy on the easiest training variant of TUNL that were overcome with training. Loss of GluN2B also impaired performance on a problem series where delay and separation were systematically varied. We also observed a training-dependent effect on performance. Mutant mice that received extensive training performed similar to control mice when challenged on a variable delay and variable separation problem, while those that received minimal training were impaired across all delays and separations. Together, these data demonstrate that GluN2B in the dorsal CA1 and cortex are essential for efficient visual-spatial discrimination learning on the TUNL task. Further, training effects on performance in mutant mice suggest that alterations in synaptic plasticity after GluN2B loss may underlie intra- versus inter-session learning.

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Section: Discussionmentioning

confidence: 99%

Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm

Kenton

Castillo

Holmes

et al. 2018

Neurobiology of Learning and Memory

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“…Changes in NMDAR subunits level have also been described following fear conditioning, Sun et al [ 49 ] have shown that there was a rapid and transient increase in the amount of membrane GluN2B-NMDARs (as both GluN1 and GluN2B increased) in CA1 area, 5 to 10 minutes after a single-trial fear conditioning training. The authors proposed that GluN1 and GluN2B increases depend on GluN2B activation, as it was blocked by GluN2B inhibitors.…”

Section: Nmdar Expression and Memory Acquisition ( Tablementioning

confidence: 99%

“…The authors proposed that GluN1 and GluN2B increases depend on GluN2B activation, as it was blocked by GluN2B inhibitors. Accordingly, Sun et al have also suggested that the reported subunit increase could depend on training strength, as a 5-trial conditioning induced higher subunits levels than a single-trial training [ 49 ].…”

Section: Nmdar Expression and Memory Acquisition ( Tablementioning

confidence: 99%

NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition

2018

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NMDA ionotropic glutamate receptors (NMDARs) are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses.

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“…Trace fear conditions increase the spiking of projection neurons in the inferior-limbic prefrontal cortex (IL-PFC) and basolateral amygdala (BLA) [20]. NMDARs are required for learning and memory and their subunits undergo dynamic modification following fear conditioning [21][22][23][24]. Inhibition of NMDARs prevents the loss of brain-derived neurotrophic factor (BDNF) function [25].…”

Section: Introductionmentioning

confidence: 99%

Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice

et al. 2019

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Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brainderived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.

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Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats

Cited by 16 publications

References 59 publications

Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm

Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm

NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition

Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice

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