Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus

Bashir, Zafar I.; Alford, Simon; Davies, Stephen N.; Randall, Andrew; Collingridge, Graham L.

doi:10.1038/349156a0

Cited by 352 publications

(147 citation statements)

References 28 publications

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“…In addition, it is now clear that NMDAR-mediated LTP and LTD also involve alterations in NMDAR-mediated EPSCs 8 . These alterations in NMDAR-mediated synaptic transmission will affect the ability of synapses to undergo subsequent synaptic plasticity and so represents a key form of metaplasticity 9 .…”

Section: Introductionmentioning

confidence: 99%

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

et al. 2010

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“…Ionotropic glutamate receptors (iGluRs) 2 are key mediators of excitatory neurotransmission, contributing to both neuronal development and adult neuroplasticity (1,2). In particular, the N-methyl-D-aspartate (NMDA) receptor subclass is responsible for initiating activity-dependent changes in synaptic strength, proposed to form the molecular basis of learning and memory (3).…”

mentioning

confidence: 99%

Constitutive Activation of the N-Methyl-d-aspartate Receptor via Cleft-spanning Disulfide Bonds

Blanke

VanDongen

2008

Journal of Biological Chemistry

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Although the N-methyl-D-aspartate (NMDA) receptor plays a critical role in the central nervous system, many questions remain regarding the relationship between its structure and functional properties. In particular, the involvement of ligandbinding domain closure in determining agonist efficacy, which has been reported in other glutamate receptor subtypes, remains unresolved. To address this question, we designed dual cysteine point mutations spanning the NR1 and NR2 ligandbinding clefts, aiming to stabilize these domains in closed cleft conformations. Two mutants, E522C/I691C in NR1 (EI) and K487C/N687C in NR2 (KN) were found to exhibit significant glycine-and glutamate-independent activation, respectively, and co-expression of the two subunits produced a constitutively active channel. However, both individual mutants could be activated above constitutive levels in a concentration-dependent manner, indicating that cleft closure does not completely prevent agonist association. Interestingly, whereas the NR2 KN disulfide was found to potentiate channel gating and M3 accessibility, NR1 EI exhibited the opposite phenotype, suggesting that the EI disulfide may trap the NR1 ligand-binding domain in a lower efficacy conformation. Furthermore, both mutants affected agonist sensitivity at the opposing subunit, suggesting that closed cleft stabilization may contribute to coupling between the subunits. These results support a correlation between cleft stability and receptor activation, providing compelling evidence for the Venus flytrap mechanism of glutamate receptor domain closure. Ionotropic glutamate receptors (iGluRs)2 are key mediators of excitatory neurotransmission, contributing to both neuronal development and adult neuroplasticity (1, 2). In particular, the N-methyl-D-aspartate (NMDA) receptor subclass is responsible for initiating activity-dependent changes in synaptic strength, proposed to form the molecular basis of learning and memory (3). Additionally, NMDA receptors have been implicated in the pathogenesis of numerous neurological disorders, including schizophrenia and Alzheimer disease, as well as neurodegeneration following ischemia or brain injury (4 -6). Despite their enormous therapeutic potential, clinical use of NMDA receptor antagonists has been limited by significant neurological side effects. However, D-cycloserine (DCS), a well tolerated partial agonist, has shown therapeutic promise as a cognitive enhancer in Alzheimer disease and head trauma recovery (7,8). Therefore, the mechanism by which glutamate receptors distinguish partial agonists from full agonists is of both scientific and medical interest.The iGluR family is composed of three subclasses, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, and NMDA receptors, all of which share the same modular domain structure. Two discontinuous segments, S1 and S2, form the ligand binding domain (LBD), whereas the ion channel portion contains three putative transmembrane segments, M1, M3, and M4, and a re-entrant loop, M2. NMDA r...

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“…For instance, the induction of LTP by high-frequency stimulation is not typically associated with a depression of NMDA receptor-mediated synaptic responses in CA1 pyramidal cells (Kauer et al 1988;Muller et al 1988;Muller and Lynch 1990;Perkel and Nicoll 1993; but see Bernard and Wheal 1995). Under some experimental conditions, highfrequency stimulation can induce LTP of NMDA receptor-mediated synaptic responses (Bashir et al 1991;Asztely et al 1992;Clark and Collingridge 1995;see also O'Conner et al 1995). Yet, highfrequency synaptic stimulation can induce metaplastic changes that inhibit the induction of additional LTP (Frey et al 1995) and/or facilitate the subsequent induction of LTD (i.e., depotentiation) (Barrionuevo et al 1980;Staubli and Lynch 1990;Fujii et al 1991;Wexler and Stanton 1993;Wagner and Alger 1995).…”

Section: Introductionmentioning

confidence: 99%

A Nitric Oxide-Independent and β-Adrenergic Receptor-Sensitive Form of Metaplasticity Limits θ-Frequency Stimulation-Induced LTP in the Hippocampal CA1 Region

Moody¹,

Carlisle²,

O’Dell³

1999

Learn. Mem.

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The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by -frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of -frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by ␤-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.

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Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus

Cited by 352 publications

References 28 publications

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

Constitutive Activation of the N-Methyl-d-aspartate Receptor via Cleft-spanning Disulfide Bonds

A Nitric Oxide-Independent and β-Adrenergic Receptor-Sensitive Form of Metaplasticity Limits θ-Frequency Stimulation-Induced LTP in the Hippocampal CA1 Region

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