Genetic enhancement of learning and memory in mice

Tang, Ya Ping; Shimizu, Eiji; Dubé, Gilles; Rampon, Claire; Kerchner, Geoffrey A.; Zhuo, Min; Liu, Guosong; Tsien, Joseph Zhuo

doi:10.1038/43432

Cited by 1,653 publications

(1,170 citation statements)

References 28 publications

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“…For example, overexpression of the NR2B subunit in mice results in enhanced learning and memory in several behavioral tasks, including fear conditioning and fear extinction (Tang et al, 1999). Further, blockade of NR2B-containing NMDARs with ifenprodil impairs synaptic plasticity in the amygdala without impairing routine neural transmission (Li et al, 1995;Weisskopf and LeDoux, 1999;Bauer et al, 2002), and ifenprodil also impairs fear acquisition without affecting its expression (Rodrigues et al, 2001;Blair et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Sotres-Bayón

Bush

LeDoux

2007

Neuropsychopharmacol

257

207

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N-methyl-D-aspartate receptors (NMDARs) contribute to synaptic plasticity underlying learning in a variety of brain systems. Fear extinction, which involves learning to suppress the expression of previously learned fear, appears to require NMDAR activation in the amygdala. However, it is unclear whether amygdala NMDARs are required for the acquisition of extinction learning, and it is unknown whether NR2B-containing NMDARs are required in fear extinction. Here, we assessed the effects of selective NR2B blockade with ifenprodil on fear extinction learning, and found that both systemic and intra-amygdala ifenprodil treatment, given before extinction training, impaired the initial acquisition, and subsequent retrieval of fear extinction. These results confirm previous evidence showing that NMDARs in the amygdala are involved in fear extinction, and additionally show that NR2B-containing NMDARs are required. Contrary to the conclusion of previous studies, our findings demonstrate NMDARs are required for the initial acquisition, rather than only the retention, of fear extinction learning. Thus, our results support a previously not known role for NMDA-dependent plasticity in the lateral amygdala during the acquisition of fear extinction.

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Section: Discussionmentioning

confidence: 99%

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Sotres-Bayón

Bush

LeDoux

2007

Neuropsychopharmacol

257

207

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“…NR2B has been shown to be necessary for synapse formation and plasticity (Tang et al, 1999;Slutsky et al, 2004), whereas NR2A expression is associated with synaptic maturation (Fu et al, 2005). NMDAR made up of NR2B and NR1 subunits are the dominant form during …”

Section: Indexing Termsmentioning

confidence: 99%

Development of NMDA R1 expression in chicken auditory brainstem

Tang

Carr

2004

Hearing Research

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N-methyl-D-aspartate (NMDA) receptor subunit-specific probes were used to characterize developmental changes in the distribution of excitatory amino acid receptors in the chicken's auditory brainstem nuclei. Although NR1 subunit expression does not change greatly during the development of the cochlear nuclei in the chicken Hear. , there are significant developmental changes in NR2 subunit expression. We used in situ hybridization against NR1, NR2A, NR2B, NR2C, and NR2D to compare NR1 and NR2 expression during development. All five NMDA subunits were expressed in the auditory brainstem before embryonic day (E) 10, when electrical activity and synaptic responses appear in the nucleus magnocellularis (NM) and the nucleus laminaris (NL). At this time, the dominant form of the receptor appeared to contain NR1 and NR2B. NR2A appeared to replace NR2B by E14, a time that coincides with synaptic refinement and evoked auditory responses. NR2C did not change greatly during auditory development, whereas NR2D increased from E10 and remained at fairly high levels into adulthood. Thus changes in NMDA NR2 receptor subunits may contribute to the development of auditory brainstem responses in the chick. Indexing termscochlear nucleus; magnocellularis; laminaris; angularis; tonotopic gradient Physiological studies have shown that the auditory system is characterized by fast, accurate encoding of auditory information (Warchol and Dallos, 1990; Zhang and Trussell, 1994a,b;Fukui and Ohmori, 2003). We have therefore investigated the distribution of subtypes of Nmethyl-D-aspartate (NMDA) receptors (NMDAR) in the brainstem auditory nuclei of the chicken to determine whether changes in receptors may reflect the development of specializations for temporal processing. NMDAR can contain two classes of subunits, NR1 and NR2 (A-D). The third class of subunits (NR3), containing NR3A and NR3B, is thought to act as modulators of the NMDAR (Ciabarra et al., 1995;Nishi et al., 2001; for review see Cull-Candy, 2001). A functional NMDAR appears to consist of two NR1 subunits and two or three NR2 subunits. NR1 is the fundamental subunit necessary for the NMDAR complex, and its expression is spatiotemporally ubiquitous compared with that of NR2 subunits in vertebrate brain (Watanabe et al., 1992;Wada et al., 2004).Changes in NMDAR composition characterize the development of forebrain circuits. NR2B has been shown to be necessary for synapse formation and plasticity (Tang et al., 1999;Slutsky et al., 2004), whereas NR2A expression is associated with synaptic maturation (Fu et al., 2005). NMDAR made up of NR2B and NR1 subunits are the dominant form during NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the "critical period" window for plasticity in mouse visual cortex (Quinlan et al., 1999a) and barrel cortex ) and in vocal learning regions of songbirds (Basham et al., 1999;Singh et al., 2000;Ding and Perkel, 2004). Near the end of the critical period, there is a gradual increase in the contribution of NR2A subunits i...

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“…Among the NR2 subunits, the NR2A and NR2B subtypes are the most prevalent in the cerebral cortex (Watanabe et al, 1992), and of the two, the NR2B subunits are shown to be particularly influential in learning and memory (Tang et al, 1999;Tang and Schuman, 2002) as they prolong NMDA receptor currents, thus allowing greater Ca influx (Mori and Mishina, 1995;Dingledine et al, 1999). Further, Roche et al (2001) have shown that the C-terminus of NR2B subunit is sufficient for rapid internalization of the NMDA receptor.…”

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confidence: 99%

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Fujisawa

Aoki

2003

Neuroscience

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We investigated the role of in vivo synaptic activity upon trafficking of the N-methyl-D-aspartate (NMDA) receptor subunit, NR2B, at mature synapses by electron microscopic immunocytochemistry. In vivo blockade of NMDA receptors was achieved by applying the NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), onto the cortical surface of one hemisphere of anesthetized adult rats. Inactive L-2-amino-5-phosphonovalerate (L-APV) was applied to the contralateral hemisphere for within-animal control and to assess basal level of NR2B subunits at synapses. Within 30 min of D-APV treatment, we observed a decrease in the number of layer I axospinous asymmetric synapses that are positively immuno-labeled for the NR2B subunits. This decrease was paralleled by reductions in the absolute number of immuno-gold particles found at these synapses. The decrease of NR2B labeling was detectable in all five animals examined. Significant reductions were seen not only at post-synaptic densities, but also within the cytoplasm of spines and axon terminals. The data demonstrate that blockade of NMDA receptors induces trafficking of NR2B subunits out of synaptic membranes, spines, and terminals. This is in sharp contrast to a previous observation that NR2A subunits move into spines and axon terminals following in vivo blockade with D-APV. These findings point to yet unknown, NMDA receptor activitydependent mechanisms that separately regulate the localization of NR2A and NR2B subunits at synapses. Keywordsactivity-dependent; D-APV; electron microscopy; immunocytochemistry; ultrastructure; postembedding colloidal gold labelingThe N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays an important role in experience-dependent plasticity. Calcium influx through this receptor can trigger a variety of downstream biochemical reactions, contributing to plasticity (Mori and Mishina, 1995;Kind and Neumann, 2001) and excitotoxicity (Lynch and Guttmann, 2002). One of many consequences of NMDA receptor activation is altered trafficking of proteins to and from the activated synapses. For example, long-term potentiation, in which the electrophysiological response to an input is augmented, is in part produced by NMDA receptor-dependent upregulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (see NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 May 24. Malenka and Nicoll, 1999). In vitro and fewer in vivo preparations have been used to demonstrate that NMDA receptors, too, are removed from or inserted into synaptic membrane (Rao and Craig, 1997;Liao et al., 1999;Quinlan et al., 1999;Heynen et al., 2000;Barria and Malinow, 2002;Grosshans et al., 2002;Tovar and Westbrook, 2002). However, since nearly all of these studies have used neonatal tissues, whether or not such dynamic properties of NMDA receptor subunits persist at mature synapses, in vivo, is a topic that remains relatively unexplored.Among the NMDA receptor subunits, the NR1 is necessary for NMD...

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Genetic enhancement of learning and memory in mice

Cited by 1,653 publications

References 28 publications

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala

Development of NMDA R1 expression in chicken auditory brainstem

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

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