Tonic Activation of NMDA Receptors by Ambient Glutamate Enhances Excitability of Neurons

Sah, Pankaj; Hestrin, Shaul; Nicoll, RA

doi:10.1126/science.2573153

Cited by 420 publications

(264 citation statements)

References 40 publications

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“…The effects of CX614 on AMPAr and PDZ proteins were partially reduced in the presence of CNQX alone, and AP-5 was less efficacious in blocking CX614 effects on AMPAr and PDZ proteins. Previous studies have demonstrated that NMDArs are tonically active in hippocampal slices (Sah et al, 1989), and our results indicated that AP-5 partially reduced CX614 effects on SAP97 and GluR2/3. In addition, AP-5 significantly decreased CX614 effects on GRIP1 but not on GluR1.…”

Section: Discussionsupporting

confidence: 75%

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Jourdi

Lü²,

Yanagihara³

et al. 2005

J Pharmacol Exp Ther

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Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2Љ,1Љ-3Ј,2Ј]1,3-oxazino[6Ј,5Ј-5,4]-benzo[e]1,4-dioxan 10-one], a positive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.AMPA-type glutamate receptors (AMPAr) mediate most of the fast excitatory neurotransmission in the mammalian central nervous system. Several recent studies have implicated the cycling of these receptors into and out of the synaptic compartment in important neurophysiological phenomena such as long-term potentiation (LTP) and long-term depression (LTD) in support of our initial hypothesis (Baudry and

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Section: Discussionsupporting

confidence: 75%

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Jourdi

Lü²,

Yanagihara³

et al. 2005

J Pharmacol Exp Ther

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“…7). This protocol permits selective activation of prefrontal afferents to the NAcore in an in vivo environment where glutamate homeostasis is not disrupted (32). We previously found a long-term potentiation (LTP)-like shift to the left of the input-output curve 3 wk after the last cocaine self-administration session (7).…”

Section: Resultsmentioning

confidence: 99%

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

Moussawi¹,

Zhou

Shen³

et al. 2010

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

163

188

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Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaineinduced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model. C ocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. An enduring cocaine-induced impairment in cognitive control of motivated behavior contributes to the vulnerability to relapse (1, 2). Projections from the frontal cortex to the basal ganglia constitute a primary brain substrate for regulating motivated behavior (3). Cocaine-induced neuropathologies in the projection from the prefrontal cortex to the nucleus accumbens are implicated in cocaine addiction (4), including impaired neuroplasticity and synaptic communication (4,5). For example, prefrontal synapses in the accumbens undergo enduring potentiation (6-9), and the ability of these synapses to increase or decrease synaptic strength is impaired (7, 10). In addition, withdrawal from chronic cocaine use increases both presynaptic release estimated by elevated frequency of miniature excitatory postsynaptic currents (mEPSC) and by postsynaptic strength measured as increases in the surface expression of AMPA glutamate receptors and the ratio of AMPA/NMDA currents at glutamatergic synapses (6,8,11).Neuroimaging in cocaine addicts reveals reduced activity in prefrontal cortex under baseline conditions, but marked hyperresponsiveness in the prefrontal cortex and accumbens that is correlated with a desire for drug upon exposure to drug-associated stimuli (12). Similarly, animal models of relapse show that activation of this pathway is necessary and sufficient to reinstate cocaine-seeking behavior (13) and that neuronal ac...

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“…Acta Pharmacologica Sinica npg tonic NMDAR activation by extracellular glutamate has been detected under basal condition [13] . Ketamine can abolish both spontaneous synaptic and extrasynaptic NMDAR responses.…”

Section: Research Highlightmentioning

confidence: 99%

Blocking NMDA receptor at rest: a possible alleviation of depression

Lü

2011

Acta Pharmacol Sin

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Tonic Activation of NMDA Receptors by Ambient Glutamate Enhances Excitability of Neurons

Cited by 420 publications

References 40 publications

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

Blocking NMDA receptor at rest: a possible alleviation of depression

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