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D G Standaert

Publications and source records attributed to D G Standaert.

At least 55 records · Page 3Linked to original sources
PubMed1998

The human N-methyl-D-aspartate receptor 2C subunit: genomic analysis, distribution in human brain, and functional expression.

cDNAs encoding four isoforms of the human NMDA receptor (NMDAR) NMDAR2C (hNR2C-1, -2, -3, and -4) have been isolated and characterized. The overall identity of the deduced amino acid sequences of human and rat NR2C-1 is 89.0%. The sequences of the rat and human carboxyl termini (Gly925-Val1,236) are encoded by different exons and are only 71.5% homologous. In situ hybridization in human brain revealed the expression of the NR2C mRNA in the pontine reticular formation and lack of expression in substantia nigra pars compacta in contrast to the distribution pattern observed previously in rodent brain. The pharmacological properties of hNR1A/2C were determined by measuring agonist-induced inward currents in Xenopus oocytes and compared with those of other human NMDAR subtypes. Glycine, glutamate, and NMDA each discriminated between hNR1A/2C-1 and at least one of hNR1A/2A, hNR1A/2B, or hNR1A/2D subtypes. Among the antagonists tested, CGS 19755 did not significantly discriminate between any of the four subtypes, whereas 5,7-dichlorokynurenic acid distinguished between hNR1A/2C and hNR1A/2D. Immunoblot analysis of membranes isolated from HEK293 cells transiently transfected with cDNAs encoding hNR1A and each of the four NR2C isoforms indicated the formation of heteromeric complexes between hNR1A and all four hNR2C isoforms. HEK293 cells expressing hNR1A/ 2C-3 or hNR1A/2C-4 did not display agonist responses. In contrast, we observed an agonist-induced elevation of intracellular free calcium and whole-cell currents in cells expressing hNR1A/2C-1 or hNR1A/2C-2. There were no detectable differences in the macroscopic biophysical properties of hNR1A/2C-1 or hNR1A/2C-2.

Amino Acid Sequence↗
PubMed1997

N-acetylaspartylglutamate (NAAG) protects against rat striatal quinolinic acid lesions in vivo.

We examined the effects of N-acetylaspartylglutamate (NAAG), an endogenous peptide thought to be involved in neurotransmission and neuromodulation, on striatal quinolinate lesions, a rodent model of Huntington's disease. We found that NAAG (500 and 1000 nmol) co-injected with quinolinic acid significantly reduced lesion volumes (by 50% and 65%, respectively). A 1000 nmol dose of the non-hydrolyzable analogue, beta-NAAG, also reduced quinolinic acid lesion volumes by 78.4%, indicating that the protection observed was not secondary to cleavage of NAAG into N-acetyl-aspartate (NAA) and glutamate. Likewise, co-injection of both NAA and glutamate (1000 nmol each) with quinolinic acid did not significantly alter the size of lesions. NAAG's protective effect may be mediated through actions on N-methyl-D-aspartate receptors or metabotropic glutamate receptors.

Animals↗
PubMed1997

Differential expression of kainate receptors in the basal ganglia of the developing and adult rat brain.

Glutamate is the principal excitatory transmitter of the mammalian brain and plays a particularly important role in the physiology of the basal ganglia structures responsible for movement regulation. Using in situ hybridization with oligonucleotide probes, we examined the expression patterns of the five known kainate type glutamate receptor subunit genes, KA1, KA2 and GluR5-7, in the basal ganglia of adult and developing rat brain. In the adult rat, a highly organized and selective pattern of expression of the kainate subunits was observed in the basal ganglia and associated structures as well as in other regions of the brain. KA2 mRNA was abundant in the striatum, nucleus accumbens, subthalamic nucleus and substantia nigra pars compacta, and was present at lower levels in the globus pallidus and substantia nigra pars reticulata. Neither KA1 nor GluR5 expression was observed in the basal ganglia of adult rats, although these messages were present in other regions. GluR6 was highly expressed in the striatum and subthalamic nucleus and to a lesser extent in the substantia nigra pars reticulata, while no hybridization signal was detectable in the large, presumably dopaminergic neurons of the substantia nigra pars compacta. In contrast, GluR7 was strongly expressed in the substantia nigra pars compacta, was present at lower levels in the striatum, globus pallidus and substantia nigra pars reticulata, and was not detectable in the subthalamic nucleus. During postnatal development, expression of the kainate receptor subunits was characteristically highest on postnatal day 1 and declined to adult levels by day 20; however, in the globus pallidus we did observe the transient expression of KA1 and GluR5 between day 1 and day 10. These results demonstrate that the neuronal structures comprising the basal ganglia express a distinct combination of kainate receptor subunit genes, suggesting that the pharmacological properties of the resultant glutamate receptors are likely to be regionally specific. The organization of expression of these genes is established early in life, which is consistent with the important role they may play in establishing the functions of the motor system.

Animals↗
PubMed1997

Huntingtin immunoreactivity in the rat neostriatum: differential accumulation in projection and interneurons.

Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D28K staining. In the matrix regions, relatively few neurons contain dense accumulations of HT-ir, and these cells always lack perikaryal staining for calbindin-D28K. Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.

Animals↗
PubMed1997

Cellular distribution of NMDA glutamate receptor subunit mRNAs in the human cerebellum.

We have used a quantitative in situ hybridization method with human ribonucleotide probes to examine the regional and cellular distribution of N-methyl-D-aspartate receptor (NMDAR) subunit mRNAs in the human cerebellum. Purkinje cells showed very dense labeling for NMDAR1 mRNA, dense labeling for NMDAR2A mRNA, and moderate labeling for NMDAR2D mRNA, whereas labeling for NMDAR2C mRNA was low. Granule cells showed high hybridization signals for the NMDAR1 and NMDAR2C mRNAs and moderate signals for the NMDAR2A and NMDAR2D mRNAs. In addition intense labeling with the NMDAR2B probe was observed in medium-sized neurons with chromophilic cell bodies in the upper part of the granule cell layer, most likely representing Golgi cells. Neurons in the molecular layer, i.e., basket cells and stellate cells, showed moderate hybridization signals for NMDAR1 and NMDAR2D and low signal for NMDAR2C. Each type of cerebellar neuron analyzed displayed a distinct NMDAR2 subunit profile, suggesting that they are likely to have NMDA receptors with distinct properties.

Cerebellar Cortex↗
PubMed1997

Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus.

Metabotropic glutamate receptors (mGluRs) can be divided into three groups based on sequence homology and pharmacology. We studied expression of group I mGluRs (mGluR1 and mGluR5) in identified neurons of the rat neostriatum, neocortex, and hippocampus using in situ hybridization. Tissue sections were hybridized with radiolabeled RNA probes for mGluR1 or mGluR5 and digoxygenin labeled RNA probes detecting somatostatin (SOM), preproenkephalin (ENK), preprotachykinin (SP), glutamic acid decarboxylase 67 (GAD67), parvalbumin (PARV), or choline acetyltransferase (ChAT) mRNA. In the striatum, mGluR1 hybridization signal was observed in all six neuronal populations. The strongest signal was found in SP-positive neurons, with a lower signal in ENK-positive neurons. All striatal interneurons were labeled less intensely than ENK- and SP-positive projection neurons. For striatal mGluR5 mRNA, both SP- and ENK-positive projection neurons were intensely labeled, but only GAD67-positive interneurons exhibited a significant signal. In the neocortex and hippocampus, mGluR1 and mGluR5 hybridization signals were studied in SOM-, GAD67-, and PARV-positive neurons. Hybridization signal for mGluR1 mRNA was intense in SOM-positive neurons of the cortex, CA1, CA3, and dentate gyrus, and weaker in GAD67-positive neurons of CA3 and dentate gyrus. MGluR5 signals were intensely labeled in SOM-, GAD67- and PARV-positive neuronal populations of the cortex and hippocampus. SOM-positive neurons were more intensely labeled in the hippocampus than cortex.

Animals↗
PubMed1996

Expression of N-methyl-D-aspartate glutamate receptor subunits in the prefrontal cortex of the rat.

The laminar distribution and cellular levels of expression of mRNAs encoding N-methyl-D-aspartate receptor subunits (NMDAR1, NMDAR2A-D and the alternatively spliced isoforms of NMDAR1) were examined in prefrontal cortex of rat by in situ hybridization using film and emulsion autoradiography. Film autoradiograms demonstrated a distinctive laminar distribution of hybridization signals for each of the probes recognizing NMDAR1, NMDAR2A, and NMDAR2B messenger RNA; hybridization with probes for NMDAR2C and NMDAR2D resulted in scattered signals without laminar organization. Grain counting disclosed that neurons in layer V displayed the highest and neurons in layer IV the lowest absolute number of grains for all probes examined. Correction for cell size demonstrated statistically significant differences in cellular labelling density of up to 50% across neurons in different cortical layers. The cellular density profiles across cortical laminae differed between probes. Hybridization with a probe recognizing all isoforms of NMDAR1 resulted in significantly lower densities of cellular labelling in neurons of layer IV than of layers II/III, V and VI. Cellular labelling densities following hybridization with probes recognizing alternatively spliced segments of NMDAR1 were examined. Densities were low in neurons of the upper cortical layers II/III and IV using probes for the messenger RNA encoding the amino terminal insert, NMDAR11XX and the second carboxy terminal deletion, NMDAR1XX1; hybridization with a probe for the messenger RNA encoding the first carboxy terminal deletion, NMDAR1X1X, resulted in low cellular signal densities in neurons of layers IV and VIb. NMDAR2A messenger RNA expression was of relatively uniform intensity in neurons of layers II-V but significantly lower in neurons of the inner part of layer VI. NMDAR2B expression was most dense in layer II neurons. These data indicate that neurons in different cortical laminae express distinct N-methyl-D-aspartate receptor subunit messenger RNA phenotypes. In addition, the observed differences in density of N-methyl-D-aspartate receptor subunit messenger RNA expression suggest that cortical laminae differ in the relative contribution of N-methyl-D-aspartate receptors to their excitatory responses.

Alternative Splicing↗
PubMed1996

Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus.

NMDA receptors are composed of proteins from two families: NMDAR1, which are required for channel activity, and NMDAR2, which modulate properties of the channels. The mRNA encoding the NMDAR2D subunit has a highly restricted pattern of expression: in the forebrain, it is found in only a small subset of cortical, neostriatal and hippocampal neurons. We have used a quantitative double-label in situ hybridization method to examine the expression of NMDAR2D mRNA in neurochemically defined populations of neurons. In the neostriatum, NMDAR2D was expressed by the interneuron populations marked by preprosomatostatin (SOM), the 67-kDa form of glutamic acid decarboxylase (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) mRNAs but not by the projection neurons expressing beta-preprotachykinin (SP) or preproenkephalin (ENK) mRNAs. In the neocortex, NMDAR2D expression was observed in only a small number of neurons, but these included almost all of the SOM-, GAD67-, and PARV-expressing interneurons. In the hippocampus, NMDAR2D was not present in pyramidal or granule cells, but was abundant in SOM-, GAD67-, and PARV-positive interneurons. NMDAR2D expression appears to be a property shared by interneurons in several regions of the brain. The unique electrophysiological characteristics conveyed by this subunit, which include resistance to blockade by magnesium ion and long channel offset latencies, may be important for the integrative functions of these neurons. NMDAR2D-containing receptor complexes may prove to be important therapeutic targets in human disorders of movement. In addition, the presence of NMDAR2D subunits may contribute to the differential vulnerability of interneurons to excitotoxic injury.

Animals↗
PubMed1996

Inhibition of N-methyl-D-aspartate glutamate receptor subunit expression by antisense oligonucleotides reveals their role in striatal motor regulation.

N-methyl-D-aspartate (NMDA) glutamate receptors have an established role in the regulation of motor behavior by the basal ganglia. Recent studies have revealed that NMDA receptors are heteromeric assemblies of structurally related subunits from two families: NMDAR1, which is required for channel activity, and NMDAR2A-D, which modulate the properties of the channels. In the rat, the NMDA receptor subunits exhibit anatomically restricted patterns of expression, so that each component of the basal ganglia has a distinct NMDA receptor subunit mRNA phenotype. We have used in vivo intrastriatal injection of synthetic antisense oligodeoxynucleotides (ODNs) to examine the roles of particular NMDA receptor subunits in the regulation of motor behavior in rats. Injection of 15 nmol of a 20-mer ODN targeted to the NMDAR1 subunit induced spontaneous ipsilateral rotation. Smaller doses of NMDAR1 antisense ODN did not lead to spontaneous rotation, but prominent ipsilateral rotation was observed after systemic administration of D-amphetamine. An antisense ODN to NMDAR2A was also effective in eliciting amphetamine-inducible rotation, although the magnitude of the effect was less than that seen with NMDAR1, whereas ODNs targeted to NMDAR2B, NMDAR2C and an NMDAR1 sense strand ODN had no effect on behavior. In situ hybridization demonstrated that injection of the NMDAR1, NMDAR2A or NMDAR2B antisense ODNs produced specific reductions in target mRNA signal intensity in the injected striatum. After NMDAR1 antisense ODN injection, striatal binding of 3H-glutamate target mRNA signal intensity in the injected striatum. After NMDAR1 antisense ODN injection, striatal binding of 3H-glutamate to NMDA sites was not altered, although strychnine-insensitive 3H-glycine binding sites exhibited a small but significant reduction. These observations suggest that NMDA receptor complexes containing NMDAR1 and, to a lesser extent, NMDAR2A subunits play particularly important roles in the regulation of motor behavior by neostriatal neurons.

Amphetamine↗
PubMed1995

Metabotropic receptors in excitotoxicity: (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) protects against rat striatal quinolinic acid lesions.

Striatal quinolinate lesions mimic many of the neuropathological characteristics of Huntington's disease. This excitotoxicity is mediated by combined activity of N-methyl-D-aspartate and metabotropic glutamate receptors (mGluRs). Using recently developed phenylglycine derivatives, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) and (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), we investigated the role of the different sub-classes of mGluRs in the in vivo excitotoxic process. (S)-4C3HPG (500 and 1000 nmol), co-injected with quinolinic acid, significantly reduced lesion volumes by 52 and 89%, respectively, whereas the same doses of (+)-MCPG had no effect on lesion size. The differential actions of these two drugs at Group 1 and Group 2 metabotropic receptors may explain their differential effects. These observations confirm the important role of mGluRs in excitotoxicity and identify them as promising targets for intervention.

Animals↗
PubMed1995

Differential expression of mGluR5 metabotropic glutamate receptor mRNA by rat striatal neurons.

Metabotropic glutamate receptors (mGluRs) mediate the effects of glutamate neurotransmission on intracellular second messenger systems. Among the seven distinct mGluR receptor isoforms currently identified, the mGluR5 isoform is expressed particularly prominently in the striatum, where it may contribute to neuronal plasticity, motor behaviors, and excitotoxic injury. mGluR5 mRNA expression in striatal enkephalinergic, somatostatinergic, and cholinergic neurons was examined using double label in situ hybridization techniques. mGluR5 expression is abundant in a large number of medium-sized striatal cells but is absent in a significant minority of neurons. Double label in situ hybridization with 35S-dATP- and digoxygenin-dUTP-tailed oligonucleotide probes demonstrated that mGluR5 message is highly expressed by enkephalinergic striatal neurons but is not detectable in cholinergic or somatostatin interneurons. In addition, some nonenkephalin, presumably substance P, neurons were also strongly labeled for mGluR5. The differential expression of mGluR5 in striatal projection neurons vs. interneurons may contribute to the selective vulnerability of these neurons to disease processes.

Animals↗
PubMed1995

DNA fragmentation and immediate early gene expression in rat striatum following quinolinic acid administration.

Excitotoxic cell death is hypothesized to contribute to numerous neuropathologic conditions, including hypoxic/ischemic encephalopathy, hypoglycemia, Parkinson's disease, and Huntington's disease. Neuronal death from excitotoxic lesions has been shown to be an active process, with activation of immediate early gene transcription, resulting in secondary changes in gene expression. Another feature of neurotoxic cell death that has been examined is the presence of DNA fragmentation, which presumably indicates impending nuclear disintegration. A technique has been described for labeling fragmented DNA in situ, allowing precise determination of the anatomic and temporal distribution of neurons after an excitotoxic lesion. To investigate this phenomenon, we performed in situ nick translation on brain tissue from rats that have undergone stereotaxically placed intrastriatal quinolinic acid injections. Furthermore, in these same animals we analyzed the expression of c-fos mRNA to compare the time course and regional distribution of DNA fragmentation with immediate early gene activation after an excitotoxic lesion. Our analysis indicates that c-fos expression increases soon after quinolinic acid injection, is widespread in rat brain, but is effectively absent by 24 h postinjection. DNA fragmentation, however, is limited to striatum and is maximal at 24 h after injection. These results demonstrate the sensitivity of in situ nick translation for the detection of regional neuropathology and illustrate the temporal and spatial relationship of c-fos expression to excitotoxic neuronal death.

Animals↗
PubMed1995

NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum.

N-Methyl-D-aspartate (NMDA) receptors are enriched in the neostriatum and are thought to mediate several actions of glutamate including neuronal excitability, long-term synaptic plasticity, and excitotoxic injury. NMDA receptors are assembled from several subunits (NMDAR1, NMDAR2A-D) encoded by five genes; alternative splicing gives rise to eight isoforms of subunit NMDAR1. We studied the expression of NMDA receptor subunits in neurochemically identified striatal neurons of adult rats by in situ hybridization histochemistry using a double-labeling technique. Enkephalin-positive projection neurons, somatostatin-positive interneurons, and cholinergic interneurons each have distinct NMDA receptor subunit phenotypes. Both populations of striatal interneurons examined express lower levels of NMDAR1 and NMDAR2B subunit mRNA than enkephalin-positive neurons. The three striatal cell populations differ also in the presence of markers for alternatively spliced regions of NMDAR1, suggesting that interneurons preferentially express NMDAR1 splice forms lacking one (cholinergic neurons) or both (somatostatin-positive neurons) alternatively spliced carboxy-terminal regions. In addition, somatostatin- and cholinergic-, but not enkephalin-positive neurons express NMDAR2D mRNA. Thus, these striatal cell populations express different NMDAR-subunit mRNA phenotypes and therefore are likely to display NMDA channels with distinct pharmacological and physiological properties. Differences in NMDA receptor expression may contribute to the relative resistance of striatal interneurons to the neurotoxic effect of NMDA receptor agonists.

Animals↗
PubMed1994

Glutamate receptor expression in rat striatum: effect of deafferentation.

The cerebral cortex is the primary source of glutamatergic afferents to the neostriatum. We used in situ hybridization to examine the effect of removal of the glutamatergic input to the striatum by unilateral frontal cortical ablation on the expression of genes encoding subunits from three families of glutamate receptors: N-methyl-D-aspartate receptors (NMDAR1, NMDAR2A, and NMDAR2B); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (GluR1-4, flip and flop splice variants); and metabotropic receptors (mGluR1-5). Significant changes were restricted to the dorsolateral quadrant of the ipsilateral striatum, the main projection area of the sensorimotor cortex. The expression of those messages which are normally abundant, NMDAR1, NMDAR2A, GluR1-4 flop and mGluR1, 3 and 5, was decreased in the deafferented dorsolateral striatum by 10-39% at 3 days after cortical ablation and subsequently increased to 120-165% of control at 15 and 60 days. mRNAs encoding the flip isoforms of GluR1-4, mGluR2 and 4, and an alternatively spliced region of NMDAR1 (Insertion I) which are undetectable or present at low levels in the striatum were not induced by cortical ablation. In contrast, both glial fibrillary acid protein and beta-actin mRNA expression were markedly enhanced at 3 and 15 days, returning to near normal at 60 days. Striatal NMDA, AMPA and metabotropic type 1 ligand binding sites were increased as early as 3 days after cortical ablation, reached a peak at 15 days and remained increased for up to 60 days, while metabotropic type 2 binding was slightly but significantly reduced at 3 and 15 days and [3H]kainate binding did not change significantly. These results demonstrate that cortical ablation, and subsequent loss of glutamatergic afferents to the striatum, results in alterations in the expression of genes encoding glutamate receptor subunits in striatal neurons. The regulation of these genes appears to be coordinate, so that the relative abundance of the different messages is preserved.

Animals↗
PubMed1994

Organization of N-methyl-D-aspartate glutamate receptor gene expression in the basal ganglia of the rat.

Glutamate is an important neurotransmitter in the circuitry of the basal ganglia. Of the four pharmacological classes of receptors that may mediate the actions of glutamate, the N-methyl-D-aspartate (NMDA) type is of particular interest insofar as it has been implicated in the neural processes underlying long-term synaptic plasticity as well as excitotoxic injury. NMDA ligand binding sites are abundant in the structures of the basal ganglia, and NMDA receptors have been linked to neuronal excitability, neuropeptide gene expression, and regulation of dopamine release in these regions. NMDA receptors are believed to be heterooligomers of subunits from two families: NMDAR1, encoded by a single gene but alternatively spliced to produce eight distinct isoforms (NMDAR1A-H), and NMDAR2, encoded by four separate genes (NMDAR2A-D). We have used in situ hybridization with a total of 13 oligonucleotide probes to examine the expression of these genes in the rat basal ganglia. NMDAR1 subunits are expressed throughout the basal ganglia as well as in the rest of the brain; however, the alternatively spliced amino-terminal region Insertion I is abundantly expressed only in the subthalamic nucleus and is not detectable in the neostriatum, globus pallidus, or substantia nigra pars compacta. In contrast, expression of the carboxy terminus segment Deletion I is prominent in the striatum but is not observed in other elements of the basal ganglia. NMDAR2 subunits also exhibit differential expression: NMDAR2B is abundant in the striatum, but NMDAR2A is present within the striatum only at low levels. NMDAR2C is present in the substantia nigra pars compacta only, while NMDAR2D exhibits an unusual distribution, with high levels of expression in the substantia nigra pars compacta, the subthalamic nucleus, the globus pallidus, and the ventral pallidum. Since each isoform of the NMDAR1 and NMDAR2 subunits can confer distinct properties on the resultant NMDA receptor, these data imply that there is a high degree of regional specialization in the properties of NMDA receptors within the basal ganglia.

Animals↗
PubMed1994

Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat.

Metabotropic glutamate receptors (mGluRs) have been implicated in a number of hippocampal functions including learning and memory. Five subtypes have been molecularly and pharmacologically characterized. Using in situ hybridization with oligonucleotide probes selective for these five mGluRs, we have found that each has a unique pattern of expression in the hippocampus and entorhinal cortex. mGluR1 is expressed predominantly in the dentate gyrus and CA3. mGluR2 is enriched in the dentate gyrus and inner layer of the entorhinal cortex. mGluR3 is also expressed in these two structures, but unlike all the other mGluRs, is found in white matter areas as well. mGluR4 is present predominantly in CA2 while mGluR5 is concentrated in most regions of the hippocampus and entorhinal cortex. Comparative analysis of the distributions of these receptors with that of the components of their putative downstream signal transduction mechanisms suggests that mGluR5 may be the main subtype of mGluR which mediates the excitatory actions of glutamate in CA1 and could contribute to the elevation of calcium levels found in CA1 pyramidal neurons in long term potentiation and in ischemic/hypoxic injury. mGluR2 and mGluR3, the main subtypes contributing to the inhibitory actions of glutamate, are absent in CA1. Thus, the mGluR-mediated excitatory actions of glutamate can occur in all regions of the hippocampus whereas the mGluR-mediated inhibitory actions of glutamate may be restricted to the dentate gyrus and CA3.

Animals↗
PubMed1994

Metabotropic glutamate receptors are differentially regulated during development.

The postnatal expression of metabotropic glutamate receptors was studied in rat brain by in situ hybridization and autoradiographic binding techniques. The messenger RNAs encoding five metabotropic glutamate receptor subtypes named mGluR1-5 had distinct regional and temporal expression profiles. mGluR1, mGluR2 and mGluR4 messenger RNA expression was low at birth and increased during postnatal development. In contrast, mGluR3 and mGluR5 were highly expressed at birth and decreased during maturation to adult levels of expression. [3H]Glutamate binding competition studies in developing brain disclosed the presence of two types of binding sites with the pharmacological properties of metabotropic glutamate receptors, having high (metabotropic type-1 binding sites; K1 = 8 nM) and low affinity (metabotropic type-2 binding sites; K1 = 50 microM) for quisqualic acid, as in adult rat brain. The densities of metabotropic binding sites changed during development in a complex, regionally specific fashion. Metabotropic type-1 binding sites were present at low levels at birth and gradually increased during the second postnatal week. In the striatum, globus pallidus and cerebellar granule layer, the increase in density of metabotropic type-1 binding sites was transient but persisted in the cerebellar molecular layer. In contrast, metabotropic type-2 binding sites were present at high densities in most regions in the first postnatal week and decreased during the second and third week, particularly in the thalamic reticular nucleus and globus pallidus. Only in the external cortex did both metabotropic type-1 and metabotropic type-2 binding sites increase during development. A striking correspondence between the temporal pattern of expression of specific metabotropic glutamate receptor transcripts and metabotropic binding sites was observed in the reticular nucleus of the thalamus (mGluR3; metabotropic type-2 binding sites) and cerebellum (mGluR1; metabotropic type-1 binding sites) suggesting early translation of these metabotropic glutamate receptor messenger RNAs into receptor proteins. In other regions the relationship between messenger RNA expression and binding sites was less direct: comparison between expression of metabotropic glutamate receptor messenger RNA and binding sites suggests both a pre- and postsynaptic location of some receptor subtypes. These data imply a functional role of mGluR3 and mGluR5 during synaptogenesis and maintenance of adult synapses and of mGluR1, mGluR2 and mGluR4 in mature synaptic transmission.

Animals↗