@article{2610, abstract = {To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7 -/-). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7 -/-, but not in mGluR7 +/-, mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7 -/- mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs.}, author = {Sansig, Gilles and Bushell, Trevor and Clarke, Vernon and Rozov, Andrei and Burnashev, Nail and Portet, Chantal and Gasparini, Fabrizio and Schmutz, Markus and Klebs, Klaus and Shigemoto, Ryuichi and Flor, Peter and Kühn, Rainer and Knoepfel, Thomas and Schroeder, Markus and Hampson, David and Collett, Valerie and Zhang, Congxiao and Duvoisin, Robert and Collingridge, Graham and Van Der Putten, Herman}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {22}, pages = {8734 -- 8745}, publisher = {Society for Neuroscience}, title = {{Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7}}, doi = {10.1523/JNEUROSCI.21-22-08734.2001}, volume = {21}, year = {2001}, } @article{2609, abstract = {The metabotropic glutamate receptors (mGluRs) have distinct distribution patterns in the CNS but subtypes within group I or group III mGluRs share similar ultrastructural localization relative to neurotransmitter release sites: group I mGluRs are concentrated in an annulus surrounding the edge of the postsynaptic density, whereas group III mGluRs are concentrated in the presynaptic active zone. One of the group II subtypes, mGluR2, is expressed in both pre- and postsynaptic elements, having no close association with synapses. In order to determine if such a distribution is common to another group II subtype, mGluR3, an antibody was raised against a carboxy-terminus of mGluR3 and used for light and electron microscopic immunohistochemistry in the mouse CNS. The antibody reacted strongly with mGluR3, but it also reacted, though only weakly, with mGluR2. Therefore, to examine mGluR3-selective distribution, we used mGluR2-deficient mice as well as wild-type mice. Strong immunoreactivity for mGluR3 was found in the cerebral cortex, striatum, dentate gyrus of the hippocampus, olfactory tubercle, lateral septal nucleus, lateral and basolateral amygdaloid nuclei, and nucleus of the lateral olfactory tract. Pre-embedding immunoperoxidase and immunogold methods revealed mGluR3 labeling in both presynaptic and postsynaptic elements, and also in glial profiles. Double labeling revealed that the vast majority of mGluR3 in presynaptic elements is not closely associated with glutamate and GABA release sites in the striatum and thalamus, respectively. However, in the spines of the dentate granule cells, the highest receptor density was found in perisynaptic sites (20% of immunogold particles within 60 nm from the edge of postsynaptic membrane specialization) followed by a decreasing receptor density away from the synapses (to ∼5% of particles per 60 nm). Furthermore, 19% of immunogold particles were located in asymmetrical postsynaptic specialization, indicating an association of mGluR3 to glutamatergic synapses. The present results indicate that the localization of mGluR3 is rather similar to that of group I mGluRs in the postsynaptic elements, suggesting a unique functional role of mGluR3 in glutamatergic neurotransmission in the CNS.}, author = {Tamaru, Y and Nomura, Sakashi and Mizuno, Noboru and Shigemoto, Ryuichi}, issn = {0306-4522}, journal = {Neuroscience}, number = {3}, pages = {481 -- 503}, publisher = {Elsevier}, title = {{Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: Differential location relative to pre- and postsynaptic sites}}, doi = {10.1016/S0306-4522(01)00305-0}, volume = {106}, year = {2001}, } @article{2608, abstract = {The regulation of neurotransmitter receptors during synapse formation has been studied extensively at the neuromuscular junction, but little is known about the development of excitatory neurotransmitter receptors during synaptogenesis in central synapses. In this study we show qualitatively and quantitatively that a receptor undergoes changes in localisation on the surface of rat Purkinje cells during development in association with its excitatory synapses. The presence of mGluR1α at parallel and climbing fibre synapses on developing Purkinje cells was studied using high-resolution immunoelectron microscopy. Immunoreactivity for mGluR1α was detected from embryonic day 18 in Purkinje cells, and showed dramatic changes in its localisation with age. At early postnatal ages (P0 and P3), mGluR1α was found both in somata and stem dendrites but was not usually associated with synaptic contacts. At P7, mGluR1α became concentrated in somatic spines associated with climbing fibres and in the growing dendritic arborisation even before innervation by parallel fibres. During the second and third postnatal week, when spines and parallel fibre synapses were generated, mGluR1α became progressively concentrated in the molecular layer, particularly in the synaptic specialisations. As a result, during the fourth postnatal week, the pattern and level of mGluR1α expression became similar to the adult and mGluR1α appeared in high density in perisynaptic sites. Our results indicate that mGluR1α is present in the developing Purkinje cells prior to their innervation by climbing and parallel fibres and demonstrate that this receptor undergoes a dynamic and specific regulation during postnatal development in association with the establishment of synaptic inputs to Purkinje cell.}, author = {López Bendito, Guillermina and Shigemoto, Ryuichi and Luján, Rafael and Juíz, José}, issn = {0306-4522}, journal = {Neuroscience}, number = {2}, pages = {413 -- 429}, publisher = {Elsevier}, title = {{Developmental changes in the localisation of the mGluR1α subtype of metabotropic glutamate receptors in Purkinje cells}}, doi = {10.1016/S0306-4522(01)00188-9}, volume = {105}, year = {2001}, } @article{2607, abstract = {Alternative splicing in the mGluR5 gene generates two different receptor isoforms, of which expression is developmentally regulated. However, little is known about the functional significance of mGluR5 splice variants. We have examined the functional coupling, subcellular targeting, and effect on neuronal differentiation of epitope-tagged mGluR5 isoforms by expression in neuroblastoma NG108-15 cells. We found that both mGluR5 splice variants give rise to comparable [Ca2+]i transients and have similar pharmacological profile. Tagged receptors were shown by immunofluorescence to be inserted in the plasma membrane. In undifferentiated cells the subcellular localization of the two mGluR5 isoforms was partially segregated, whereas in differentiated cells the labeling largely redistributed to the newly formed neurites. Interestingly, we demonstrate that mGluR5 splice variants dramatically influence the formation and maturation of neurites; mGluR5a hinders the acquisition of mature neuronal traits and mGluR5b fosters the elaboration and extension of neurites. These effects are partly inhibited by MPEP.}, author = {Mion, Silvia and Corti, Corrado and Neki, Akio and Shigemoto, Ryuichi and Corsi, Mauro and Fumagalli, Guido and Ferraguti, Francesco}, issn = {1044-7431}, journal = {Molecular and Cellular Neuroscience}, number = {6}, pages = {957 -- 972}, publisher = {Academic Press}, title = {{Bidirectional regulation of neurite elaboration by alternatively spliced metabotropic glutamate receptor 5 (mGluR5) isoforms}}, doi = {10.1006/mcne.2001.0993}, volume = {17}, year = {2001}, } @article{2605, abstract = {The granular layer of the cerebellar cortex consists of densely packed neuronal cells, classified into granule cells and large interneurons. In this study, we provide a comparative survey of large granular layer interneurons in the adult rat cerebellum based on both morphological and neurochemical criteria. To this end, double immunofluorescence histochemistry was performed by combining antibodies against the cytoplasmic antigen Rat-303, calretinin, the metabotropic glutamate receptor mGluR2 and somatostatin. Based on Rat-303/calretinin double immunohistochemistry, three distinct populations of large granular layer interneurons could be discerned: cells immunopositive for Rat-303, calretinin or both. Rat-303 or calretinin single-labeled cells represented Golgi cells and unipolar brush cells, respectively. Rat-303/calretinin double-labeled cells located just underneath the Purkinje cell layer represented Lugaro cells. Morphometrical analysis distinguished two populations of Rat-303-positive Golgi cells according to their location: vermis versus hemisphere. Immunostaining for the metabotropic glutamate receptor mGluR2 combined with Rat-303 or calretinin revealed that the majority of Golgi cells (about 90%) appeared to be mGluR2 positive. Lugaro cells were mGluR2 negative. In addition, a limited population of large polymorphous interneurons in the depth of the granular layer with morphological features resembling Golgi cells also displayed Rat-303/calretinin immunoreactivity and were mGluR2 negative. Double immunohistochemistry for Rat-303 and somatostatin revealed three populations of labeled cells in the depth of the granular layer. Besides double-labeled Golgi cells, Rat-303 or somatostatin single-labeled cells were present. Based on mGluR2/somatostatin and calretinin/somatostatin double immunostainings, Rat-303 single-labeled cells were found to correspond to Rat-303/calretinin-positive, mGluR2-negative Golgi-like cells, while the identity of somatostatin single-labeled cells remained unclear. The data presented in this article elaborate previous reports on the morphological and neurochemical differentiation of large interneurons in the rat cerebellar granular layer. In addition, they indicate that the current classification of these cells into Golgi cells, Lugaro cells and unipolar brush cells does not describe the observed neurochemical heterogeneity.}, author = {Geurts, Frederik and Timmermans, Jean and Shigemoto, Ryuichi and De Schutter, Erik}, issn = {0306-4522}, journal = {Neuroscience}, number = {2}, pages = {499 -- 512}, publisher = {Elsevier}, title = {{Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum}}, doi = {10.1016/S0306-4522(01)00058-6}, volume = {104}, year = {2001}, }