Kainate Glutamate Receptor Research Articles

Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression.

Polyunsaturated fatty acids (PUFA) are essential structural components of the central nervous system. Their role in controlling learning and memory has been well documented. A nutrigenomic approach with high-density microarrays was used to reveal brain gene-expression changes in response to different PUFA-enriched diets in rats. In aged rats fed throughout life with PUFA-enriched diets, genes with altered expressions included transthyretin, alpha-synuclein, and calmodulins, which play important roles in synaptic plasticity and learning. The effect of perinatal omega-3 PUFA supply on gene expression later in life also was studied. Several genes showed similar changes in expression in rats fed omega-3-deficient diets in the perinatal period, regardless of whether they or their mothers were fed omega-3 PUFA-sufficient diets after giving birth. In this experiment, among the down-regulated genes were a kainate glutamate receptor and a DEAD-box polypeptide. Among the up-regulated genes were a chemokine-like factor, a tumor necrosis factor receptor, and cytochrome c. The possible involvement of the genes with altered expression attributable to different diets in different brain regions in young and aged rats and the possible mode of regulatory action of PUFA also are discussed. We conclude that PUFA-enriched diets lead to significant changes in expression of several genes in the central nervous tissue, and these effects appear to be mainly independent of their effects on membrane composition. The direct effects of PUFA on transcriptional modulators, the downstream developmentally and tissue-specifically activated elements might be one of the clues to understanding the beneficial effects of the omega-3 PUFA on the nervous system.

Astrocyte-mediated activation of neuronal kainate receptors.

Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca(2+)-dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca(2+) in astrocytes, induced by uncaging Ca(2+), o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-d-aspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca(2+) elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca(2+) uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca(2+) uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA/kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.

Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons.

Plasticity in gene expression is achieved by a complex array of molecular mechanisms by which intracellular signaling pathways directly govern transcriptional regulation. In addition to the remarkable variety of transcription factors and co-regulators, and their combinatorial interaction at specific promoter loci, the role of chromatin remodeling has been increasingly appreciated. The N-terminal tails of histones, the building blocks of nucleosomes, contain conserved residues that can be post-translationally modified by phosphorylation, acetylation, methylation and other modifications. Depending on their nature, these modifications have been linked to activation or silencing of gene expression. We wanted to investigate whether neuronal stimulation by various signaling pathways elicits chromatin modifications that would allow transcriptional activation of immediate early response genes. We have analysed the capacity of three drugs - SKF82958 (a dopaminergic receptor agonist), pilocarpine (a muscarinic acetylcholine receptor agonist) and kainic acid (a kainate glutamate receptor agonist) - to induce chromatin remodeling in hippocampal neurons. We show that all stimulations induce rapid, transient phosphorylation of histone H3 at serine 10. Importantly, the same agonists induce rapid activation of the mitogen-activated protein kinase pathway with similar kinetics to extracellular-regulated-kinase phosphorylation. In the same neurons where this dynamic signaling cascade is activated, there is induction of c-fos transcription. Histone H3 Ser10 phosphorylation is coupled to acetylation at the nearby Lys14 residue, an event that has been linked to local opening of chromatin structure. Our results underscore the importance of dynamic chromatin remodeling in the transcriptional response to various stimuli in neuronal cells.

Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats.

This study investigated the role of ionotropic and metabotropic glutamate receptors in the deficits in brain reward function, as measured by elevations in intracranial self-stimulation (ICSS) reward thresholds, associated with nicotine withdrawal. The group II metabotropic glutamate (mGluII) receptor agonist LY314582 [a racemic mixture of LY354740 ([+]-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid])] (2.5-7.5 mg/kg) precipitated withdrawal-like elevations in ICSS thresholds, a sensitive measure of reward function, in nicotine-dependent but not control rats. LY314582 did not affect response latencies, a measure of performance in the ICSS paradigm. Bilateral microinfusion of LY314582 (10-100 ng/side) into the ventral tegmental area likewise precipitated dose-dependent threshold elevations in nicotine-dependent rats. Furthermore, a single injection of the mGluII receptor antagonist LY341495 (2S-2-amino-2-[1S,2S-2-carboxycyclopropan-1-yl]-3-[xanth-9-yl]propionic acid) (1 mg/kg) attenuated the threshold elevations observed in rats undergoing spontaneous nicotine withdrawal. mGluII receptors are primarily located on glutamatergic terminals throughout the mesocorticolimbic system, where they act as inhibitory autoreceptors. To investigate whether mGluII receptors contributed to nicotine withdrawal by decreasing glutamatergic transmission, we next examined whether direct blockade of postsynaptic glutamate receptors precipitated withdrawal-like reward deficits in nicotine-dependent rats. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX; 0.01-1 mg/kg) precipitated withdrawal-like threshold elevations in nicotine-dependent but not control rats, whereas 6-methyl-2-[phenylethynyl]-pyridine (MPEP; 0.01-3 mg/kg) and dizocilpine (MK-801; 0.01-0.2 mg/kg), antagonists at metabotropic glutamate 5 and N-methyl-d-aspartate receptors, respectively, did not. Overall, these data demonstrate that mGluII receptors play an important role in the reward deficits associated with nicotine withdrawal. Furthermore, it is likely that mGluII receptors generate this reward deficit, at least in part, by decreasing glutamate transmission at AMPA/kainate receptors.

The role of spinal neurokinin-1 and glutamate receptors in hyperalgesia and allodynia induced by prostaglandin E 2 or zymosan in the rat

Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia. This study sought to establish whether neurokinin-1 (NK-1) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E 2 (PGE 2) in rats, and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan, an inflammatory agent which is known to evoke spinal PGE 2 release. Spinal application of antagonists of the NK-1 receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of PGE 2 or intraplantar administration of zymosan. The decrease in thermal paw withdrawal response latencies induced by PGE 2, but not by zymosan, was significantly attenuated by spinal administration of an N-methyl- d-aspartate (NMDA) receptor antagonist, an AMPA/kainate receptor antagonist, or a metabotropic glutamate receptor antagonist. Allodynia induced by PGE 2 was significantly alleviated by antagonists of NMDA or AMPA/kainate receptors. These results suggest that both PGE 2-induced and zymosan-induced mechanical hyperalgesia are mediated in part through activation of NK-1, AMPA/kainate and metabotropic glutamate receptors. PGE 2-induced, but not zymosan-induced, thermal hyperalgesia is mediated in part by activation of NMDA, AMPA/kainate and metabotropic glutamate receptors. Activation of both NMDA and AMPA/kainate receptors contribute to PGE 2-induced allodynia.

Mechanism-based pain diagnosis: issues for analgesic drug development.

Mechanism-based pain diagnosis: issues for analgesic drug development.

Effect of ionotropic glutamate receptors antagonists on the modifications in extracellular glutamate and aspartate levels during picrotoxin seizures: a microdialysis study in freely moving rats

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(−)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(−)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.

Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus.

Fast excitatory neurotransmission in the central nervous system occurs at specialized synaptic junctions between neurons, where a high concentration of glutamate directly activates receptor channels. Low-affinity AMPA (alpha-amino-3-hydroxy-5-methyl isoxazole propionic acid) and kainate glutamate receptors are also expressed by some glial cells, including oligodendrocyte precursor cells (OPCs). However, the conditions that result in activation of glutamate receptors on these non-neuronal cells are not known. Here we report that stimulation of excitatory axons in the hippocampus elicits inward currents in OPCs that are mediated by AMPA receptors. The quantal nature of these responses and their rapid kinetics indicate that they are produced by the exocytosis of vesicles filled with glutamate directly opposite these receptors. Some of these AMPA receptors are permeable to calcium ions, providing a link between axonal activity and internal calcium levels in OPCs. Electron microscopic analysis revealed that vesicle-filled axon terminals make synaptic junctions with the processes of OPCs in both the young and adult hippocampus. These results demonstrate the existence of a rapid signalling pathway from pyramidal neurons to OPCs in the mammalian hippocampus that is mediated by excitatory, glutamatergic synapses.

Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata

The substantia nigra pars reticulata belongs to the brain regions with the highest density of CB 1 cannabinoid receptors. Since the level of CB 1 receptor messenger RNA is very low in the pars reticulata, most of the receptors are probably localized on terminals of afferent axons. The hypothesis was tested that terminals of glutamatergic afferents of substantia nigra pars reticulata neurons possess CB 1 cannnabinoid receptors, the activation of which presynaptically modulates neurotransmission. Rat midbrain slices were superfused and the electrophysiological properties of substantia nigra pars reticulata neurons were studied with the patch-clamp technique. Focal electrical stimulation in the presence of bicuculline evoked excitatory postsynaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors. The excitatory postsynaptic currents were reduced by the metabotropic glutamate receptor agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (trans-ACPD; 10 -4 M). The mixed CB 1/CB 2 cannabinoid receptor agonists R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone (WIN55212-2; 10 −8–10 −5 M) and (−)- cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]- trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; 10 −6 M) also produced inhibition. The maximal inhibition by WIN55212-2 was 54±6%. The CB 1 cannabinoid antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716A; 10 −6 M) prevented the effect of WIN55212-2, but had no effect when superfused alone. WIN55212-2 (10 −6 M) increased the amplitude ratio of two excitatory postsynaptic currents evoked with an interstimulus interval of 100 ms. Currents evoked by short ejection of glutamate on to the surface of the slices were not changed by WIN55212-2. The results show that activation of CB 1 cannabinoid receptors inhibits glutamatergic synaptic transmission between afferent axons and neurons in the substantia nigra pars reticulata. The lack of effect of the cannabinoids on glutamate-evoked currents and the increase of the paired-pulse ratio indicate that the mechanism of action is presynaptic inhibition of transmitter release.

Expression and localization of ionotropic glutamate receptor subunits in the goldfish retina--an in situ hybridization and immunocytochemical study.

The expression and distribution of AMPA, kainate and NMDA glutamate receptor subunits was studied in the goldfish retina. For the immunocytochemical localization of the AMPA receptor antisera against GluR2, GluR2/3 and GluR4 were used, and for in situ hybridization rat specific probes for GluR1 and GluR2 and goldfish specific probes for GluR3 and GluR4 were used. The localization of the low affinity kainate receptor and NMDA receptor was studied using antisera against GluR5-7 and NR1. All AMPA receptor subtypes were demonstrated to be present in the goldfish retina both by immunocytochemistry and in situ hybridization. In situ hybridization revealed expression of all AMPA receptors subunit at the inner border of the INL. Only GluR3 was also strongly expressed in the outer border of the INL. Some of the ganglion cells displayed a strong signal for GluR1, GluR3 and GluR4. GluR1-immunoreactivity was present in subsets of bipolar, amacrine, and ganglion cells. GluR2 and GluR2/3-immunoreactivity was mainly localized in the outer plexiform layer. GluR2 and GluR2/3-immunoreactivity are associated with the photoreceptor synaptic terminals. GluR4-immunoreactivity is present on Müller cells in the inner retina and on dendrites of bipolar cells in the OPL, whereas GluR5-7-immunoreactivity was prominently present on horizontal cell axon terminals. Finally, NR1-immunoreactivity was confined to amacrine cells, the inner plexiform layer and ganglion cells. This study shows that there is a strong heterogeneity of glutamate receptor subunit expression in the various layers of the retina. Of the AMPA receptor subunits GluR3 seems to be expressed the most widely in all layers with strong glutamatergic synaptic interactions whereas all the other subunits seem to have a more restricted expressed pattern.

D 2 dopamine receptor but not AMPA and kainate glutamate receptor genes show altered expression in response to long term treatment with trans- and cis-flupenthixol in the rat brain

Glutamate receptor function has been hypothesized as an important factor in both the aetiology and treatment of schizophrenia. We have used a multiprobe oligonucleotide solution hybridization (MOSH) technique to examine the regulation of gene expression of the GluR1–7, KA1, and KA2 glutamate receptor subunits in the left rat brain following treatment with the optical isomers of flupenthixol at a dose of 0.2 mg kg −1 day −1 over a period of 4, 12, 24 weeks in order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia. The GluR2/3 and GluR6/7 subunit immunoreactivity in the right brain following 4 and 24 weeks of drug treatment was also examined by Western blotting. Neither trans- nor cis-flupenthixol was found to alter the gene expression of any of the 9 non-NMDA glutamate receptor subunits. On the other hand, we found a nearly two-fold increase in gene expression of the D 2 dopamine receptor in specific brain regions. These results suggest that non-NMDA types of glutamate receptor subunits, in contrast to NMDA receptors, are less likely to have a role in the action of antipsychotic drugs.

Kainate glutamate receptors (GluR5-7) in the rat arcuate nucleus: relationship to tanycytes, astrocytes, neurons and gonadal steroid receptors.

Glutamate action, through its ionotropic, kainate receptors, has been implicated in gonadal steroid-dependent mechanisms of the arcuate nucleus. The objective of the present study was to determine the expression of kainate glutamate receptors in neural and glial elements of this area and their potential relationship to gonadal steroid receptors. Single and double label, light and electron microscopic immunocytochemistry for kainate glutamate receptors and estrogen or androgen receptors revealed the existence of glutamate (GluR) 5-7 kainate receptors in tanycytes, astrocytes and neurons of the arcuate nucleus. In the arcuate nucleus, subsets of GluR5-7-containing neurons were also immunopositive for estrogen (20%) and/or androgen receptors (23%). Glial elements, however, lacked labeling for gonadal steroid receptors. The coexistence of gonadal and kainate receptors in the same perikarya of arcuate nucleus cell populations suggests hormone regulation of excitatory neurotransmission through ionotropic glutamate receptors in these regions. It is also indicated that a kainate receptor-mediated glutamate action may participate in neuro-glial interaction in the arcuate nucleus that, in turn, may underlie the morphological synaptic plasticity induced by gonadal steroids.

Regional vulnerability to endogenous and exogenous oxidative stress in organotypic hippocampal culture.

Organotypic cultures of the brain provide a unique opportunity to directly examine the regional vulnerability of specific brain regions like the hippocampus. Two well-characterized models of oxidative stress were used to examine the regional vulnerability of the hippocampus. Endogenous oxidative stress was induced by blocking synthesis of the endogenous antioxidant, glutathione with buthionine sulfoximine (BSO). Exogenous oxidative stress was induced with paraquat, an intracellular generator of superoxide. Injury was measured by quantitative fluorescence microscopy using the vital dye propidium iodide. BSO caused dose- and time-dependent injury that took at more than 24 h to develop. Injury began in discrete patches in the culture. In any given culture, each patch increased in size and intensity as incubation continued. The pattern was not clearly correlated with neuronal anatomy and may demonstrate glial vulnerability. Injury caused by BSO could be prevented with the antioxidants trolox or the 21-aminosteroid U-83836E, both of which are vitamin E derivatives. Paraquat also caused dose- and time-dependent injury, but the CA1 region of the hippocampus was most vulnerable. The same pattern of selective CA1 injury was caused by brief exposures to high concentrations and by prolonged exposures to much lower concentrations. Under some conditions, paraquat injury was prevented by iron chelation with deferoxamine or by blockade of either NMDA or AMPA/ kainate glutamate receptors. During paraquat exposure, glutathione concentration in the cultures was reduced prior to onset of propidium staining. The observation that the hippocampus has a similar selective regional pattern of vulnerability to paraquat and ischemia suggests that their mechanisms of injury may be related.

Feeding induced by blockade of AMPA and kainate receptors within the ventral striatum: a microinfusion mapping study

The corticostriatal pathway is believed to utilize the excitatory amino acid glutamate as its transmitter, and the striatum contains high levels of all glutamate receptor subtypes. It has recently been demonstrated that blockade of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate receptors in the medial part of the accumbens, corresponding to the medial shell subregion, results in a pronounced feeding response. In order to more precisely localize this response, a microinfusion mapping study was conducted. Bilateral microinfusions of 6,7-dinitroquinoxaline-2,3-dione (DNQX, 0, 50, 250, 750 ng/0.5 μl), an antagonist that blocks AMPA and kainate receptors, were carried out in eight striatal subregions in different groups of animals. In non-deprived rats, food intake (normal chow), feeding duration, and several other behavioral measures were assessed during a 30 min test session. DNQX significantly and potently enhanced food intake when injected into the accumbens shell, but not into any other region examined, including accumbens core, anterior dorsal, posterior dorsal, ventromedial, dorsomedial, and ventrolateral striatum. The most sensitive site within the accumbens was found to be the posterior aspects of the shell, in which the lowest dose (50 ng DNQX) augmented feeding. These results suggest that a circumscribed region within the nucleus accumbens has a unique role in the control of feeding. It is postulated that removal of tonic excitatory inputs to this region with DNQX results in disinhibition of brain circuits critical for ingestive behavior.

Ontogeny of non-NMDA glutamate receptors in rat barrel field cortex: II. ?-ampa and kainate receptors

The ontogeny of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA) glutamate receptors in rat barrel field cortex was characterized by using receptor autoradiography and immunocytochemistry. A somatotopic pattern of AMPA receptors with fewer [3H]AMPA sites in barrel centers than in surrounding cortex did not emerge until postnatal day 10 (P10). After reaching a peak density at P14, the density of [3H]AMPA receptors declined in both barrel centers and surrounding cortex. Compared with AMPA receptors, the density of [3H]KA sites at all ages was low, a somatotopic expression of [3H]KA sites was missing, and the developmental curve for [3H]KA sites was more shallow than that for [3H]AMPA binding sites. A differential ontogeny of AMPA and KA receptors in barrel field cortex was also demonstrated in immunocytochemical studies with antibodies to the AMPA receptor subunits GluR1 and GluR2,3 and the KA receptor subunits GluR6,7. GluR1 and GluR2,3 staining was more dense in barrel septa than in barrel centers; this pattern persisted into adulthood. GluR1 and GluR2,3 receptors were localized to cell bodies and dendrites as well as the neuropil, but different populations of cortical neurons expressed these receptors. At P10, KA receptor subunits GluR6,7 exhibited a contrasting pattern to that of AMPA receptor subunits, with slightly more neuropil staining in barrel centers than in surrounding cortex. After that point, the somatotopic pattern of GluR6,7 subunit expression was lost. The contrasting developmental patterns of expression of the AMPA and KA receptors in the barrel field suggest that they may play different roles in the whisker-to-barrel pathway.

Topiramate: current status and therapeutic potential

Topiramate (TPM) is a structurally unique, highly effective new antiepileptic drug (AED). Three mechanisms of action that may contribute to TPM anticonvulsant activity include modulation of voltage-dependent sodium channels, potentiation of gamma-aminobutyric acid (GABA)-induced chloride fluxes and blockade of kainate glutamate receptors. TPM is rapidly absorbed, has linear pharmacokinetics, a half-life of 20 - 30 h in the absence of hepatic-enzyme-inducing AEDs, and few pharmacokinetic interactions with other drugs. TPM is not extensively metabolised and is excreted renally. The most common adverse effects reported in controlled trials were mild to moderate in severity, mainly CNS-related, and occurred most frequently during the titration period when the TPM dosage was rapidly increased. Combined data from five double-blind, placebo-controlled trials showed TPM produced statistically significant reductions in seizures regardless of age, gender or baseline seizure frequency. Seizure control appears to be maintained with long-term TPM therapy; no evidence of tolerance was seen in patients receiving TPM for periods of up to 7 years. Preliminary findings on TPM as monotherapy for partial epilepsy and as adjunctive therapy for generalised tonic-clonic seizures of non-focal origin, Lennox-Gastaut syndrome, and partial epilepsy in children have been promising.

Expression of glutamate receptor subunit genes during development of the mouse retina.

The distribution of expression during retinal differentiation of nine AMPA and kainate glutamate receptor subunit genes was studied by in situ hybridization. Transcripts encoding all subunits were detected in the inner nuclear and ganglion cell layers of the developing mouse retina, but their time courses of expression differed. The earliest expression was detected at embryonic day 14 (E14) for GluR1, GluR4 and KA-2; all the other subunits were first detected at E16. Most subunits were expressed at higher levels during development than in the adult. This suggests they play a role in the processes of neuronal differentiation and synaptogenesis that occur during the early postnatal days in the rodent retina.

Unilateral eyeball enucleation differentially alters AMPA-, NMDA- and kainate glutamate receptor binding in the newborn rat brain

The aim of the present work was to evaluate the neurochemical effects of early unilateral visual deprivation as a model of impaired visual maturation. For this purpose, binding to the different ionotropic glutamate receptor subtypes was quantified in vision-related and vision-unrelated brain structures of control and unilaterally deprived newborn rats. At post-natal (PN) day 10, male Sprague-Dawley rats underwent either unilateral eyeball enucleation (enucleation group, n = 12) or sham operation (control group, n = 12). In each group, brains were obtained either post-natal day 20 ( n = 6) or post-natal day 30 ( n = 6) and processed for quantitative in vitro autoradiography selective for NMDA, kainate, and AMPA glutamate-binding sites, as well as for the presynaptic adenosine A1 receptor as a control of the deafferentation efficacy. In control animals, quantitative autoradiography revealed an increase in NMDA (e.g. +45% in superior colliculus) and kainate receptor binding (e.g. +55% in visual cortex, layer IV) from post-natal day 20 to post-natal day 30, associated with stable levels of AMPA receptor binding, in the vision-related structures. In the deafferented visual structures, monocular enucleation induces a marked decrease in A1 site density (e.g. −38 to − 52%, in the superficial layer of superior colliculi, at PN day 20 and PN day 30, respectively) in parallel with a mild increase in both NMDA (e.g. + 8 to 9%, in superior colliculi and visual cortex, layer IV at PN day 30, respectively) and AMPA (e.g. +16%, in layer IV of the visual cortex at PN day 30). Superimposed on marked bilateral decreases at PN day 30 in the enucleated rats, kainate receptor binding also revealed a slight but significant decrease (−5%) in the deafferented superior colliculus as compared to the non-deafferented side. The present findings (different time-courses of, and differential effects of deafferentation on, the NMDA, kainate and AMPA glutamate receptor subtypes throughout the visual brain structures) further support the involvement of these receptors in distinctive roles during maturation of the visual system.

Activation of AMPA and kainate glutamate receptors impairs the viability of oligodendrocytes in vitro.

Activation of AMPA and kainate glutamate receptors impairs the viability of oligodendrocytes in vitro.

Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus

The nucleus accumbens in a brain region considered to be important in the regulation of appetitive behavior and reinforcement. The accumbens receives afferent input from corticolimbic and thalamic structures, which is primarily coded by excitatory amino acids (EAAs). The present studies investigated the role of EAA input to the nucleus accumbens in feeding behavior in rats, in two recently characterized subregions of the accumbens, the "core" and "shell". In the first series of experiments, it was shown that blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate receptors in the medial part of the accumbens, corresponding to the medial shell subregion, resulted in a pronounced feeding response. Bilateral microinfusion of 6,7-dinitroquinoxaline-2,3-dione (DNQX, 0.25-0.75 micrograms/0.5 microliters), 6-cyano-7-nitroquinoxaline (CNQX, 0.75-1.5 micrograms), and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-(F) quinoxaline (NBQX, 0.2-1.0 micrograms) markedly stimulated food intake immediately following infusion, in a dose-dependent manner. Infusion of DNQX into the central accumbens region, corresponding to the core, did not elicit feeding. Infusion of the NMDA antagonists 2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 (dizocilpine maleate) did not elicit feeding in either region. The feeding response to DNQX was blocked by local coinfusion of AMPA. Systemic pretreatment with naltrexone (5 mg/kg) had no effect on the DNQX-feeding response; however, prior systemic administration of both D-1 and D-2 antagonists reduced the response by half, suggesting a modulatory role for dopamine in the response. Moreover, the feeding response was completely inhibited by concurrent infusion of the GABAA agonist muscimol (10, 25 ng) into the lateral hypothalamus, a major projection area of the accumbens shell. These findings demonstrate a selective role for non-NMDA receptors in the nucleus accumbens shell in ingestive behavior, and suggest an important functional link between two major brain regions involved in reward, the nucleus accumbens and lateral hypothalamus.