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Spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate acute spinal processing of nociceptive and non-nociceptive information, but whether and how their activation contributes to the central sensitization that underlies persistent inflammatory pain are still unclear. Here, we examined the role of spinal AMPARs in the development and maintenance of complete Freund's adjuvant (CFA)-induced persistent inflammatory pain. Intrathecal application of two selective non-competitive AMPAR antagonists, CFM-2 (25 and 50 microg) and GYKI 52466 (50 microg), significantly attenuated mechanical and thermal hypersensitivities on the ipsilateral hind paw at 2 and 24 h post-CFA injection. Neither CFM-2 nor GYKI 52466 affected the contralateral basal responses to thermal and mechanical stimuli. Locomotor activity was not altered in any of the drug-treated animals. CFA-induced inflammation did not change total expression or distribution of AMPAR subunits GluR1 and GluR2 in dorsal horn but did alter their subcellular distribution. The amount of GluR2 was markedly increased in the crude cytosolic fraction and decreased in the crude membrane fraction from the ipsilateral L4-5 dorsal horn at 24 h (but not at 2 h) post-CFA injection. Conversely, the level of GluR1 was significantly decreased in the crude cytosolic fraction and increased in the crude membrane fraction from the ipsilateral L4-5 dorsal horn at 24 h (but not at 2 h) post-CFA injection. These findings suggest that spinal AMPARs might participate in the central spinal mechanism of persistent inflammatory pain.
We compared the toxin sensitivity, Ca2+ flux response and rectification properties of recombinant alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors obtained by transfecting human embryonic kidney (HEK) 293 cells with different ratios of GluR1 and GluR2 cDNAs (10:1 to 1:10). Simultaneous measurements of kainate-activated Ca2+ fluxes and inward currents, using fura-2 microfluorimetry under voltage clamp conditions, suggested the existence of GluR2 containing channels which are permeable to Ca2+ and insensitive to Joro spider toxin (JSTx). Imaging experiments showed that JSTx inhibition of the Ca2+ response induced by kainate was reduced by increasing the relative amount of GluR2. However, even at GluR1/GluR2(R) ratios of 1:1 and 1:4, cells were still able to flux Ca2+ when stimulated by kainate. GluR2 similarly inhibited the ability of JSTx to reduce kainate-evoked inward currents in whole cell patch-clamp experiments. Variations in the rectification properties of the AMPA currents, induced by changes in the cDNA ratio, were not always correlated with the changes in toxin sensitivity and [Ca2+]i response. Thus, cells with almost linear I-V relationships were partially blocked by JSTx and still Ca2+ permeable. Our results indicate a dissociation between the toxin sensitivity and Ca2+ flux through GluR2 containing AMPA receptors and suggest that receptors with diverse Ca2+ permeabilities are generated by the expression of variable amounts of GluR2.
Endocytosis of GluA2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in CA1 of the hippocampus regulates forgetting; deficits in forgetting nociceptive memory can induce serious stress disorders. As a transporter of GluA2-containing AMPAR, the functions of glutamate receptor interacting protein 1 (GRIP1) in forgetting and possible stress responses remain unclear. Lentivirus-mediated interference of GRIP1 expression or function in the dorsal CA1 of the hippocampus in mice indicated that GRIP1 overexpression enhanced spatial memory, impaired forgetting in a Barnes maze, and induced anxiety-like behavior in the open field and elevated plus-maze test. In contrast, GRIP1 knockdown impaired learning capacity. Furthermore, inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 and GluA2-dn enhanced learning capacity, whereas GluA2-dn impaired spatial memory; inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 also decreased forgetting capacity to some extent. Importantly, inhibition of both the PDZ2 and PDZ4/5 domains of GRIP1 induced anxiety-like behavior but not GluA2-dn. Furthermore, optogenetic control of both GluA1 and GluA2 insertion into the postsynaptic membrane impaired memory and induced anxiety-like behavior. In vitro experiments showed that GRIP1-ov and -dn, inhibition of PDZ2 and PDZ4/5 domains of GRIP1, and GluA2-dn decreased glycine-induced GluA1 and GluA2 exocytosis; meanwhile, GRIP1-ov and -dn, and interference of PDZ2 and PDZ4/5 domains of GRIP1 blocked AMPA- and NMDA-induced GluA1 and GluA2 endocytosis. Overall, these results suggest that GRIP1 drives AMPA receptor endocytosis and exocytosis bidirectionally; furthermore, GRIP1-induced stabilization of anchoring postsynaptic GluA1 and GluA2 impairs forgetting and induces anxiety-like behavior. GRIP1 may provide a potential therapeutic target in posttraumatic syndromes and anxiety disorders.
Dopamine depletion leads to impaired motor performance and increased glutamatergic-mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In the present study, we investigated the effect of high-intensity treadmill exercise on changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input-output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine-sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline-treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.
1. CGP 40116 is the active (R)-enantiomer of the most potent N-methyl-D-aspartic acid (NMDA) receptor antagonist presently available: 2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849). In this study, we describe the effect of CGP 40116 on whole-cell currents induced by excitatory amino acids in cultured mouse spinal cord cells by use of the whole-cell patch-clamp technique. 2. We found that application of CGP 40116 in the nM range, concentration-dependently inhibited whole-cell current evoked by 20 microM NMDA in mouse cultured spinal neurones (IC50 +/- s.e. mean 48 +/- 8 nm CGP 40116). 3. The compound appeared to be highly selective for the NMDA current. At concentrations as high 1 microM, currents evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid were not affected by CGP 40116. The threshold concentration for antagonism of NMDA-induced responses was 10 nM suggesting a selectivity ratio of > or = 100 fold for NMDA receptors versus AMPA or kainate receptors. 4. CGP 40116 produced a parallel rightward displacement of the NMDA log concentration-current curve indicating competitive antagonism at the transmitter recognition site of the NMDA receptor complex. An apparent dissociation constant for the antagonist was calculated from the displacement of the agonist concentration-current curve: 117 +/- 53 nM CGP 40116 (estimated Kd +/- s.e.). Like other competitive NMDA antagonists, CGP 40116 blocked NMDA-evoked current in a voltage-independent manner.
The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are important glutamatergic receptors mediating fast excitatory synaptic transmission in the brain. The regulation of the four subunits of AMPA receptors, GluA1-4, is poorly understood. Excitatory synaptic transmission is highly energy-demanding, and this energy is derived mainly from the oxidative pathway. Recently, we found that specificity factor regulates all subunits of cytochrome c oxidase (COX), a critical energy-generating enzyme. COX is also regulated by nuclear respiratory factor 1 (NRF-1), which transcriptionally controls the Gria2 (GluA2) gene of AMPA receptors. The goal of the present study was to test our hypothesis that Sp-factors (Sp1, Sp3, and/or Sp4) also regulate AMPA subunit genes. If so, we wish to determine if Sp-factors and NRF-1 function via a complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel mechanism. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, we found that Sp4, but not Sp1 or Sp3, regulates the Gria2, but not Gria1, 3, or 4, subunit gene of the AMPA receptor in a concurrent and parallel manner with NRF-1. Thus, Sp4 and NRF-1 both mediate the tight coupling between neuronal activity and energy metabolism at the transcriptional level.
The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) class of ionotropic glutamate receptors comprises four different subunits: iGluR1/iGluR2 and iGluR3/iGluR4 forming two subgroups. Three-dimensional structures have been reported only of the ligand-binding core of iGluR2. Here, we present two X-ray structures of a soluble construct of the R/G unedited flip splice variant of the ligand-binding core of iGluR4 (iGluR4(i)(R)-S1S2) in complex with glutamate or AMPA. Subtle, but important differences are found in the ligand-binding cavity between the two AMPA receptor subgroups at position 724 (Tyr in iGluR1/iGluR2 and Phe in iGluR3/iGluR4), which in iGluR4 may lead to displacement of a water molecule and hence points to the possibility to make subgroup specific ligands.
N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.
Blockade of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors is a good treatment option for a variety of central nervous system disorders. The present study evaluated the neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, as a potential drug candidate.
Patients suffering from encephalitis may present psychiatric symptoms; however, the clinical relevance of anti-neuronal antibodies in patients experiencing a psychotic episode without encephalitis is still unclear. In this study, we examined the presence of anti-neuronal cell surface autoantibodies and onconeural autoantibodies in serum samples of 22 synthetic cannabinoid users presenting with psychosis. We found only two positive cases; however, seven patients had borderline results. Nonetheless, we found no significant correlation between anti-neuronal autoantibodies and the intensity of psychosis indicated by the Positive and Negative Syndrome Scale (PANSS) scores. The length of drug use and the combination of other drugs with synthetic cannabinoids have no significant effect on anti-neuronal autoantibody positivity. Nonetheless, the ratio of anti-citrate synthase (anti-CS) IgM and IgG natural autoantibodies was significantly lower (p = 0.036) in the anti-neuronal autoantibody-positive/borderline samples, than in the negative group. Interestingly, anti-CS IgM/IgG showed a significant negative correlation with PANSS-positive score (p = 0.04, r = -0.464). Our results demonstrated that anti-neuronal autoantibody positivity occurs in synthetic cannabinoid users, and the alteration of anti-CS IgM/IgG natural autoantibody levels points to immunological dysfunctions in these cases.
Previous findings, mainly in in vitro systems, have shown that the density of vesicles and the synaptic efficacy at excitatory synapses are reduced in the absence of synapsins, despite the fact that transgenic mice lacking synapsins develop an epileptic phenotype. Here we study glutamate receptors by quantitative immunoblotting and by quantitative electron microscopic postembedding immunocytochemistry in hippocampus of perfusion fixed control wild type and double knock-out mice lacking synapsins I and II. In wild type hippocampus the densities of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits were higher (indicated for glutamate receptor subunit 1, highly significant for glutamate receptor subunits 2/3) in mossy fiber-to-cornu ammonis 3 pyramidal cell synapses than in the Schaffer collateral/commissural-to-cornu ammonis 1 pyramidal cell synapses, the two synapse categories that carry the main excitatory throughput of the hippocampus. The opposite was true for N-methyl-D-aspartate receptors. The difference in localization of glutamate receptor subunit 1 receptor subunits was increased in the double knock-out mice while there was no change in the overall expression of the glutamate receptors in hippocampus as shown by quantitative Western blotting. The increased level of glutamate receptor subunit 1 at the mossy fiber-to-cornu ammonis 3 pyramidal cell synapse may result in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with reduced proportions of glutamate receptor subunit 2, and hence increased Ca2+ influx, which could cause increased excitability despite of impaired synaptic function (cf. [Krestel HE, Shimshek DR, Jensen V, Nevian T, Kim J, Geng Y, Bast T, Depaulis A, Schonig K, Schwenk F, Bujard H, Hvalby O, Sprengel R, Seeburg PH (2004) A genetic switch for epilepsy in adult mice. J Neurosci 24:10568-10578]), possibly underlying the seizure proneness in the synapsin double knock-out mice. In addition, the tendency to increased predominance of N-methyl-d-aspartate receptors at the main type of excitatory synapse onto cornu ammonis 1 pyramidal cells might contribute to the seizure susceptibility of the synapsin deficient mice. The results showed no significant changes in the proportion of 'silent' Schaffer collateral/commissural synapses lacking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors or in the synaptic membrane size, indicating that plasticity involving these parameters is not preferentially triggered due to lack of synapsins.
Dynamic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) underlies aspects of synaptic plasticity. Although numerous AMPAR-interacting proteins have been identified, their quantitative and relative contributions to native AMPAR complexes remain unclear. Here, we quantitated protein interactions with neuronal AMPARs by immunoprecipitation from brain extracts. We found that stargazin-like transmembrane AMPAR regulatory proteins (TARPs) copurified with neuronal AMPARs, but we found negligible binding to GRIP, PICK1, NSF, or SAP-97. To facilitate purification of neuronal AMPAR complexes, we generated a transgenic mouse expressing an epitope-tagged GluR2 subunit of AMPARs. Taking advantage of this powerful new tool, we isolated two populations of GluR2 containing AMPARs: an immature complex with the endoplasmic reticulum chaperone immunoglobulin-binding protein and a mature complex containing GluR1, TARPs, and PSD-95. These studies establish TARPs as the auxiliary components of neuronal AMPARs.
We exposed murine cortical neuronal cell cultures for 24 hours to defined concentrations of N-methyl-D-aspartate (NMDA), kainate, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and assessed the resultant neuronal degeneration quantitatively by the efflux of lactate dehydrogenase to the bathing medium. The small subpopulations of neurons that stained immunohistochemically for either somatostatin- or parvalbumin-like reactivity were atypically affected by these excitotoxins. Limited exposure to kainate or AMPA did little damage to the general neuronal population, but destroyed nearly all somatostatin- or parvalbumin-reactive cells. Conversely, these immunoreactive cells were more resistant to NMDA-induced injury than the general population. In view of reports suggesting that somatostatin- and parvalbumin-reactive cortical neurons may be preferentially damaged in Alzheimer's disease, these observations support a hypothesis that the overactivation of non-NMDA receptors could be involved in Alzheimer's disease pathogenesis.
The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.
Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Furthermore, GluA1 knockout mice showed decreased extracellular signal-regulated kinase (ERK) phosphorylation in the ACC in inflammatory pain models in vivo. Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.
Synaptic loss underlies the memory deficit of Alzheimer's disease (AD). The molecular mechanism is elusive; however, excitatory synapses organized by the postsynaptic density (PSD) have been used as targets for AD treatment. To identify pathological entities at the synapse in AD, synaptic proteins were screened by quantitative proteomic profiling. The critical proteins were then selected for immunoblot analysis. The glutamate receptors N-methyl-d-aspartate (NMDA) receptor 1 and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2 (GluR2) were substantially lost; specifically, the loss of GluR2 was up to 40% at PSD in AD. Shank proteins, the organizers of these glutamate receptors at excitatory synapses, were dramatically altered in AD. The level of Shank2 was increased, whereas the protein level of Shank3 was decreased. Further, the Shank3 protein was modified by ubiquitin, indicating that abnormal activity of the ubiquitin-proteasome system may lead to Shank3 degradation in AD. Our findings suggest that disruption of glutamate receptors at the Shank-postsynaptic platform could contribute to destruction of the PSD which underlies the synaptic dysfunction and loss in AD.
Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels.
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