Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) γ−8 Through Investigations of TARP γ−8 Null Mice§
Scott D. GleasonAkihiko KatoHai H. BuiLinda ThompsonSabrina ValliPatrick V. StutzMing‐Shang KuoJulie F. FalconeWesley H. AndersonXia LiJeffrey M. Witkin
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Transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) γ-8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP γ-8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP γ-8 by comparing the wild type (WT) and γ-8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the γ-8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP γ-8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice.Keywords:
NBQX
The neuroprotective properties of the N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) and the non-NMDA antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) and α-methyl-4-carboxyphenylglycine (MCPG) were evaluated against neuronal injury produced by the intraspinal injection of NMDA and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). Forty-nine animals were divided into eight groups in order to evaluate the effects of different drug combinations: (a) NMDA; (b) NMDA+MCPG; (c) NMDA+NBQX; (d) NMDA+MK-801; (e) AMPA; (f) AMPA+MCPG; (g) AMPA+MK-801; and (h) AMPA+NBQX. Drugs were microinjected into spinal segments T12-L3 through a micropipette attached to a Hamilton microliter syringe. Spinal cords were evaluated after a survival period of 48 h at which time NMDA and AMPA were found to produce morphological changes over the concentration ranges of 125–500 mM and 75–500 μM, respectively. Neuronal loss following injections of NMDA+MK-801 or AMPA+NBQX was significantly less than that following injections of NMDA or AMPA alone. By contrast, neuronal loss following co-injections of NMDA or AMPA with inappropriate antagonists, i.e., NMDA+NBQX/MCPG or AMPA+MCPG/MK-801, was not significantly different from that produced by NMDA or AMPA. The results suggest that elevations in spinal levels of glutamate followed by prolonged activation of NMDA and AMPA receptor subtypes initiate an excitotoxic cascade resulting in neuronal injury. Blockade of NMDA and AMPA effects by MK-801 and NBQX respectively confirms the well documented neuroprotective effects of these drugs and lends support to the potential importance of NMDA and especially AMPA receptor antagonists as therapeutic agents in the treatment of acute spinal cord injury.
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Receptor agonist/antagonist mediated modulation of the excitotoxic effect of AMPA was studied in organotypic hippocampal slice cultures. Treatment of developing cultures for 2 weeks with a subtoxic dose of 2 μM kainate reduced the toxicity of 3 μM AMPA, applied for 48 h with 24 h of recovery, as measured by cellular uptake of the fluorescent dye propidium iodide. In contrast long-term treatment with 0.3μM of the AMPA/KA antagonist NBQX increased the susceptibility of the cultures to an even lower dose of 2 μM AMPA. The modulatory effects of long-term application of low doses of kainate and NBQX, have implications for the development and use of related drugs that aim to protect against glutamate receptor-mediated disturbances.
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We have studied the effect of two glutamate receptor antagonists on seizures and hippocampal neurone loss in the rat after systemic kainic acid administration. Intraperitoneal injection of the novel AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione) (30 mg/kg x 3 and 15 mg/kg x 3) administered 30 and 15 min. before and simultaneously with injection of kainic acid (5 mg/kg) intraperitoneally, dramatically enhanced the toxicity of kainic acid leading to death of all animals. When the NBQX dose was reduced to 8 mg/kg x 3, all animals survived and neurone damage in the hippocampus did not differ from control animals. When NBQX (30 mg/kg x 3) was administered 30- or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone loss. Post-kainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min. after intraperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely prevented. The results emphasize the importance of the NMDA-receptor activation for seizure generation and subsequent brain damage after intraperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral ischaemia and hypoglycaemia, conditions which are also characterized by glutamate-mediated damage. One possible explanation of the lowered seizure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal cells.
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Pharmacologically-induced persistent hippocampal γ oscillation in area CA3 requires activation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs). However, we demonstrated that exogenous AMPA dose-dependently inhibited carbachol (CCH)-induced γ oscillation in the CA3 area of rat hippocampal slices, but the underlying mechanism is not clear. Application of AMPARs antagonist NBQX (1 μM) did not affect γ oscillation power (γ power), nor AMPA-mediated γ power reduction. At 3 μM, NBQX had no effect on γ power but largely blocked AMPA-mediated γ power reduction. Ca2+-permeable AMPA receptor (CP-AMPAR) antagonist IEM1460 or CaMKK inhibitor STO-609 but not CaMKIIα inhibitor KN93 enhanced γ power, indicating that activation of CP-AMPAR or CaMKK negatively modulated CCH-induced γ oscillation. Either CP-AMPAR antagonist or CaMKK inhibitor alone did not affected AMPA-mediated γ power reduction, but co-administration of IEM1460 and NBQX (1 μM) largely prevented AMPA-mediated downregulation of γ suggesting that CP-AMPARs and CI-AMPARs are involved in AMPA downregulation of γ oscillation. The recurrent excitation recorded at CA3 stratum pyramidale was significantly reduced by AMPA application. Our results indicate that AMPA downregulation of γ oscillation may be related to the reduced recurrent excitation within CA3 local neuronal network due to rapid CI-AMPAR and CP-AMPAR activation.
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The secretion of PRL is controlled by different hypothalamic signals. Depending on the experimental model, PRL secretion increases or decreases after activation of N-methyl-d -aspartic acid and kainate receptors. Recently we have described that activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors inhibits PRL secretion in prepubertal male rats. The aim of present study was to examine (1) the physiological relevance of this finding, (2) the possible age-related changes observed after activation or blockade of AMPA receptors, (3) the specificity of the AMPA effect, (4) the hypothalamic and/or pituitary localization of AMPA action, and (5) the mechanism(s) of action of AMPA agonists. In a first set of experiments, neonatal males (5 and 10 days old) and prepubertal (23 days old) male rats were injected with AMPA (1, 2.5 or 5 mg/kg) or the antagonist of AMPA receptors 1,2,3, 4-tetrahydro-6-nitro-2,3-dioxo-! benzo (f) quinoxaline-7-sulfonamide (NBQX; 0.25 or 0.50 mg/kg). Serum PRL concentrations decreased significantly 15 and 30 min after i.p. administration of AMPA in prepubertal male rats, while the inhibitory effect of AMPA was not observed in 5- and 10-day-old males. The effect of AMPA was abolished by NBQX but not by MK-801 (a selective antagonist of NMDA receptors). NBQX alone (0.25 or 0.50 mg/kg) had no effect on PRL release. In vitro, AMPA slightly stimulated PRL secretion by hemipituitaries from prepubertal males, suggesting that the hypothalamus is likely the site of action for the reported inhibitory action of AMPA on PRL release. In this sense, the blockade of AMPA effects in animals pretreated with domperidone (a dopaminergic antagonist) or alpha-methyl-p-tyrosine (an inhibitor of dopamine synthesis) suggests that an increase in the release of hypothalamic dopamine is probably the mechanism i! nvolved in the effect of AMPA. In a second set of experiments, the effects of AMPA (2.5 mg/kg i.p.) and NBQX (0.5 mg/kg i.p. and 20 or 40 nmol i.c.v.) were tested in freely moving adult male rats sampled during periods of 2, 3 or 6 h. In contrast with data obtained in prepubertal rats, neither AMPA nor NBQX affected PRL secretion. In conclusion, these data indicate that activation of AMPA receptors inhibits PRL secretion in prepubertal male rats. This effect probably involves the release of dopamine from the hypothalamus and disappears in adulthood.
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