Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit

Tovar, Kenneth R.; Sprouffske, Kathleen; Westbrook, Gary L.

doi:10.1152/jn.2000.83.1.616

Cited by 64 publications

(45 citation statements)

References 20 publications

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“…Recombinant NR1-NR2B receptors expressed in Xenopus oocytes elicited more robust and prolonged Ca 2ϩ currents than NR1-NR2A receptors (Vicini et al, 1998;Wyllie et al, 1998). Similarly, NMDA receptor-mediated EPSCs showing fast decay have been reported in cultured hippocampal neurons from NR2B-deficient mice (Tovar et al, 2000). Indeed, our maternally stressed mice retained Mg 2ϩ -and AP-5-dependent fast decaying EPSCs but lacked the slow component.…”

Section: Discussionsupporting

confidence: 74%

Maternal Stress Produces Learning Deficits Associated with Impairment of NMDA Receptor-Mediated Synaptic Plasticity

Geum²,

et al. 2006

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Stress in adulthood can have a profound effect on physiology and behavior, but the extent to which prolonged maternal stress affects the brain function of offspring when they are adult remains primarily unknown. In the present work, chronic immobilization stress to pregnant mice affected fetal growth and development. When pups born from stressed mice were reared to adulthood in an environment identical to that of nonstressed controls, several physiological parameters were essentially unaltered. However, spatial learning and memory was significantly impaired in the maternally stressed offspring in adulthood. Furthermore, electrophysiological examination revealed a significant reduction in NMDA receptor-mediated long-term potentiation in the CA1 area of hippocampal slices. Subsequent biochemical analysis demonstrated a substantial decrease in NR1 and NR2B subunits of the NMDA receptor in synapses of the hippocampus, and the interaction between these two subunits appeared to be reduced. These results suggest that prolonged maternal stress leads to long-lasting malfunction of the hippocampus, which extends to and is manifested in adulthood.

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Section: Discussionsupporting

confidence: 74%

Maternal Stress Produces Learning Deficits Associated with Impairment of NMDA Receptor-Mediated Synaptic Plasticity

Geum²,

et al. 2006

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“…Finally, the peak amplitudes of NMDA EPSCs in PFC were slightly smaller than those in V1, and smaller responses are expected to be better clamped and exhibit faster rise times (30). In our view, the slower time constant of the PFC NMDA current is likely to be the result of higher expression of NR2B subunits in PFC neurons, because NMDA current durations are largely controlled by the subunit composition of NMDARs [17,[31][32][33]. Indeed, we found that the proportion of the NMDAR current blocked by the NR2B antagonist ifenprodil was twofold higher in PFC than V1.…”

Section: Discussionmentioning

confidence: 75%

A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex

Wang

Stradtman

Wang³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

186

257

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In the prefrontal cortex, NMDA receptors are important for normal prefrontal functions such as working memory, and their dysfunction plays a key role in the pathological processes of psychiatric disorders such as schizophrenia. Little is known, however, about the synaptic properties of NMDA receptors in the local circuits of recurrent excitation, a leading candidate mechanism underlying working memory. We investigated the NMDA receptor-mediated currents at monosynaptic connections between pairs of layer 5 pyramidal neurons. We found that NMDA receptor-mediated currents at prefrontal synapses in the adult, but not young, rats exhibit a twofold longer decay time-constant and temporally summate a train of stimuli more effectively, compared to those in the primary visual cortex. Experiments with pharmacological, immunocytochemical, and biochemical approaches further suggest that, in the adult animals, neurons express significantly more NR2B subunits in the prefrontal cortex than the visual cortex. The NR2B-rich synapses in the prefrontal circuitry may be critically implicated in online cognitive computations and plasticity in learning, as well as psychiatric disorders.cortical development ͉ persistent activity ͉ working memory ͉ recurrent excitation W hat are the microcircuit properties that enable the prefrontal cortex (PFC) to subserve cognitive functions such as working memory and decision making in contrast to early sensory coding and processing in primary sensory areas? To address this central question, physiologists have focused on a salient feature of PFC, namely self-sustained persistent activity, as a candidate neural mechanism for short-term working memory in primates (1-3) and rodents (4). It has been hypothesized that persistent activity is generated by sufficiently strong recurrent excitation among prefrontal neurons (5). The N-methyl-Daspartate receptors (NMDARs) may be critically involved in persistent activity, as indicated by the findings that NMDAR antagonists impaired performance on delayed response tasks in rat PFC (6, 7). Recently, computational models confirmed that only the slow kinetics of NMDARs could stabilize the active maintenance of memory trace (8-10), and their voltage dependences could enhance the stimulus selectivity of persistent activity (11). Therefore, modeling work suggests that a distinctive feature of PFC is its slow reverberating neural dynamics that depend on the NMDARs in the local recurrent circuits.This raises the question of whether PFC neurons are endowed with a substantially higher number of NMDARs, or with NMDARs that express distinct biophysical properties, compared with those in a sensory area such as the primary visual cortex V1 (10). One anatomical study has reported a higher level of mRNA for NMDARs in PFC than in other cortices in human postmortem brain tissues (12). Physiologically, little is known about the functional properties of NMDARs in the prefrontal local recurrent circuits. Because prefrontal functions mature more slowly than the visual cortex, and thi...

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“…We find that the kinetics of the apteronotid NR1/NR2B receptor closely matched that of the murine NR1/NR2B, with essentially identical time courses for the channel deactivation. Although the deactivation time courses of the NR2A, C, and D subunits from Apteronotus have not been determined, the evolutionary conservation of the NR2B kinetics supports the idea that the relatively slow deactivation time course of the NR2B containing NMDA receptors is a critical functional property (Brockie et al 2001;Lester et al 1990;Silver et al 1992;Tovar et al 2000).…”

Section: Discussionmentioning

confidence: 96%

Excitatory Amino Acid Receptors of the Electrosensory System: The NR1/NR2BN-Methyl-d-Aspartate Receptor

Harvey‐Girard

Dunn

2003

Journal of Neurophysiology

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acid receptors of the electrosensory system: the NR1/NR2B Nmethyl-D-aspartate receptor. J Neurophysiol 89: 822-832, 2003; 10.1152/jn.00629.2002. The amino acid sequence of the N-methyl-D-aspartate (NMDA) receptor subunit NR2B from the brown ghost knife fish Apteronotus leptorhynchus has been determined and compared with the sequence of the murine NR2B. This comparison revealed high levels of sequence conservation throughout the ligand binding and membrane spanning segments. The functional properties of the NR1 and NR2B receptor complex were examined by coexpression in HEK cells. The recombinant AptNR1/NR2B receptors produced robust currents after stimulation with glutamate or NMDA in the presence of glycine. Measurements of the concentration dependencies for these agonists indicated that the agonist binding sites on the apteronotid receptor are highly conserved, with nearly identical agonist affinities to those of the murine NR1/NR2B receptor. The kinetic responses of the fish receptor were also highly conserved, with deactivation rates for the AptNR2B receptor matching those of the murine NR2B containing receptor. Evidently, most of the unique functional properties that reside in the NR2B receptor subunit have been well conserved in teleost NMDA receptors. On the other hand, the apteronitid receptor displayed a lowered sensitivity to voltagedependent Mg 2ϩ block and a reduced affinity for the NR2B-specific noncompetitive antagonist ifenprodil. We conclude that the functional properties that result from the incorporation of the NR2B receptor in the NMDA receptor complex have been maintained since the evolutionary divergence of teleost and mammalian organisms.

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Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit

Cited by 64 publications

References 20 publications

Maternal Stress Produces Learning Deficits Associated with Impairment of NMDA Receptor-Mediated Synaptic Plasticity

Maternal Stress Produces Learning Deficits Associated with Impairment of NMDA Receptor-Mediated Synaptic Plasticity

A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex

Excitatory Amino Acid Receptors of the Electrosensory System: The NR1/NR2BN-Methyl-d-Aspartate Receptor

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