Comment on "Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity"

Institute of Neurology, University College LondonQueen SquareLondon WC1N 2BG, UK.
Science (Impact Factor: 33.61). 10/2004; 305(5692):1912; author reply. DOI: 10.1126/science.1101128
Source: PubMed


Activation of N-methyl-D-aspartate subtype glutamate receptors (NMDARs) is required for long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular substrates of learning and memory. However, little is known about how activation of NMDARs leads to these two opposing forms of synaptic plasticity. Using hippocampal slice preparations, we showed that selectively blocking NMDARs that contain the NR2B subunit abolishes the induction of LTD but not LTP. In contrast, preferential inhibition of NR2A-containing NMDARs prevents the induction of LTP without affecting LTD production. These results demonstrate that distinct NMDAR subunits are critical factors that determine the polarity of synaptic plasticity.


Available from: Matthew C Walker
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    • "In agreement with this, we observed a strong reduction of dendrite branching in SOD1 G93A M1 neurons in which postsynaptic expression of NR2A is decreased. Our findings therefore agree with a scenario in which an altered NR2A expression decreases dendritic branch complexity and reduces LTP at cortical synapses, as already shown in the hippocampus both in vitro (Liu et al. 2004; Massey et al. 2004) and in vivo (Fox et al. 2006). Indeed, a direct implication of CaMKIIs signaling in Ca 2+ -dependent development of dendritic arbor in cortical neurons has also been demonstrated although other members of the CaMK family might also be involved (Wayman et al. 2008). "
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    ABSTRACT: Although amyotrophic lateral sclerosis (ALS) has long been considered as a lower motor neuron (MN) disease, degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented. The observation that these mechanisms are altered in presymptomatic superoxide dismutase (SOD1) mice, an ALS mouse model, suggests that defective primary motor cortex (M1) synaptic activity might precede the onset of motor disturbances. To examine this point, we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction from the M1 in postnatal P80-P85 SOD1(G93A) and wild-type mice. We show that presymptomatic SOD1(G93A) exhibit a selective decrease of NR2A subunit expression and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction of upper MNs synapses. These molecular alterations are associated with synaptic plasticity defects, and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms. We suggest that the progressive disruption of M1 corticocortical connections resulting from the SOD1(G93A) mutation might extend to adjacent regions and promote development of cognitive/dementia alterations frequently associated with ALS.
    Cerebral Cortex 04/2011; 21(4):796-805. DOI:10.1093/cercor/bhq152 · 8.67 Impact Factor
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    • "Besides modulating NMDA receptor function zinc also acts on other postsynaptic channels and receptors including voltage gated ion channels, GABA (γaminobutyric acid), dopamine and Trk (tyrosine kinase) receptors (Bitanihirwe and Cunningham 2009) and therefore cannot be used as a selective inhibitor for NR2A-NMDA receptors. More recent studies reported the discovery of a new NMDAR antaogonist, NVP- AAM077 ([(R)-[(S)-1-(4-bromophenyl)-ethylamino]-(2, 3-dioxo-1,2,3,4- tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid)) (Auberson et al. 2002), which was claimed to display strong selectivity for NR2A-containing NMDA receptors (Liu et al. 2004). However, its selectivity has been debated in several studies (Feng et al. 2004; Berberich et al. 2005; Weitlauf et al. 2005; Frizelle et al. 2006; Neyton and Paoletti 2006; de Marchena et al. 2008). "
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    ABSTRACT: J. Neurochem. (2010) 114, 1107–1118. NMDA receptors regulate both the activation and inactivation of the extracellular signal-regulated kinase (ERK) signaling cascade, a key pathway involved in neuronal plasticity and survival. This bi-directional regulation of ERK activity by NMDA receptors has been attributed to opposing actions of NR2A- versus NR2B-containing NMDA receptors, but how this is implemented is not understood. Here, we show that glutamate-mediated intracellular Ca2+ increases occur in two phases, a rapid initial increase followed by a delayed larger increase. Both phases of the Ca2+ increase were blocked by MK-801, a non-selective NMDA receptor inhibitor. On the other hand, selective inhibition of NR2B-NMDA receptors by Ifenprodil or Ro 25-6981 blocked the delayed larger phase but had only a small effect on the rapid initial increase. The rapid initial increase in Ca2+, presumably because of NR2A-NMDAR activation, was sufficient to activate ERK, whereas the large delayed increases in Ca2+ mediated by NR2B-NMDARs were necessary for dephosphorylation and subsequent activation of striatal-enriched phosphatase, a neuron-specific tyrosine phosphatase that in turn mediates the dephosphorylation and inactivation of ERK. We conclude that the magnitude of Ca2+ increases mediated through NR2B-NMDA receptors plays a critical role in the regulation of the serine/threonine and tyrosine kinases and phosphatases that are involved in the regulation of ERK activity.
    Journal of Neurochemistry 08/2010; 114(4):1107-18. DOI:10.1111/j.1471-4159.2010.06835.x · 4.28 Impact Factor
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    • "It is well established that synaptic NMDAR composition influences the induction of synaptic plasticity (Barria and Malinow, 2005; Gardoni et al., 2009; Jung et al., 2008; Liu et al., 2004a; Tang et al., 1999). Yet, the spatial scales of NMDAR compositional changes and the precise role of specific receptor subunits are controversial (Barria and Malinow, 2005; Jung et al., 2008; Liu et al., 2004a; Massey et al., 2004; Morishita et al., 2007; Philpot et al., 2007; Tang et al., 1999; Zhou et al., 2007). A prevailing model suggests that the relative levels of NR2A and NR2B modify the threshold for LTP and LTD induction (Kopp et al., 2006; Philpot et al., 2007; Yashiro and Philpot, 2008). "
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    ABSTRACT: Optimal function of neuronal networks requires interplay between rapid forms of Hebbian plasticity and homeostatic mechanisms that adjust the threshold for plasticity, termed metaplasticity. Numerous forms of rapid synapse plasticity have been examined in detail. However, the rules that govern synaptic metaplasticity are much less clear. Here, we demonstrate a local subunit-specific switch in NMDA receptors that alternately primes or prevents potentiation at single synapses. Prolonged suppression of neurotransmitter release enhances NMDA receptor currents, increases the number of functional NMDA receptors containing NR2B, and augments calcium transients at single dendritic spines. This local switch in NMDA receptors requires spontaneous glutamate release but is independent of action potentials. Moreover, single inactivated synapses exhibit a lower induction threshold for both long-term synaptic potentiation and plasticity-induced spine growth. Thus, spontaneous glutamate release adjusts plasticity threshold at single synapses by local regulation of NMDA receptors, providing a novel spatially delimited form of synaptic metaplasticity.
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