200 results found
Wisden W, Farrant M, 2002, Insights into GABA-A receptor complexity from the study of cerebellar granule cells: synaptic and extrasynaptic receptors., Glutamate and GABA receptors and transporters, Editors: Egebjerg, Krogsgaard-Larsen, Schousboe, Publisher: CRC, Pages: 189-201, ISBN: 9780748408818
This book conveys recent discoveries in a framework of the basic concepts in the fieldof glutamate and GABA receptor research.
Bedford FK, Kittler JT, Muller E, et al., 2001, GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1, NATURE NEUROSCIENCE, Vol: 4, Pages: 908-916, ISSN: 1097-6256
Brickley SG, Revilla V, Cull-Candy SG, et al., 2001, Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance, NATURE, Vol: 409, Pages: 88-92, ISSN: 0028-0836
Campos ML, De Cabo C, Wisden W, et al., 2001, Expression of GABA(A) receptor subunits in rat brainstem auditory pathways: Cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus, NEUROSCIENCE, Vol: 102, Pages: 625-638, ISSN: 0306-4522
Wisden W, Seeburg PH, Monyer H, 2000, Chapter IV AMPA, kainate and NMDA ionotropic glutamate receptor expression-an in situ hybridization atlas, Handbook of Chemical Neuroanatomy, Vol: 18, Pages: 99-143, ISSN: 0924-8196
Most rat neocortical neurons have Ca2+-impermeable AMPA receptors containing GluR-A/B, heteromeric receptors will be least numerous in layer IV cells (Fig. 11) (discussed by Conti et al., 1994a). Most GABAergic interneurons have Ca2+-permeable AMPA receptors made from GluR-A/D subunits; these receptors will have fast kinetics and high single-channel conductance. © 2000 Elsevier B.V. All rights reserved.
Wisden W, Seeburg PH, Monyer H, 2000, AMPA, kainate and NMDA ionotropic glutamate receptor expression: an in situ hybridization atlas., Glutamate, Editors: Ottersen, Storm-Mathisen, Publisher: Elsevier Science Ltd, Pages: 99-143, ISBN: 9780444502865
The volume presents a comprehensive and up-to-date treatise of the glutamatergic synapse and its environment.
Jones A, Paterlini M, Wisden W, et al., 2000, Transgenic methods for directing gene expression to specific neuronal types: cerebellar granule cells, 2nd Symposium on Cerebellar Modules, Publisher: ELSEVIER SCIENCE BV, Pages: 69-80, ISSN: 0079-6123
Wisden W, 2000, Technical workshop: Ligand-gated ion channel diversity, Publisher: BLACKWELL SCIENCE LTD, Pages: 382-382, ISSN: 0953-816X
Jones A, Paterlini M, Wisden W, et al., 2000, Transgenic methods for directing gene expression to specific neuronal types: cerebellar granule cells., Progress in Brain Resaerch: Cerebellar modules: molecules, morphology and function, Editors: Gerrits, Ruigrok, De Zeeuw, Pages: 69-80, ISBN: 9780444801043
Merlo D, Brickley SG, Farrant M, et al., 2000, GABA-A receptor diversity: a view from the cerebellum., GABA in the nervous system: the view at fifty years, Editors: Martin, Olsen, Publisher: Lippincott Williams and Wilkins, Pages: 369-382
Mellor JR, Wisden W, Randall AD, 2000, Somato-synaptic variation of GABA(A) receptors in cultured murine cerebellar granule cells: investigation of the role of the alpha6 subunit, Neuropharmacology, Vol: 39, Pages: 1495-1513, ISSN: 0028-3908
Electrophysiological investigation of cultured cerebellar murine granule cells revealed differences between the GABA(A) receptors at inhibitory synapses and those on the cell body. Specifically, mIPSCs decayed more rapidly than cell body receptors deactivated, the mean single channel conductance at the synapse (32 pS) was greater than that at cell body (21 pS) and only cell body receptors were sensitive to Zn(2+) (150 microM), which depressed response amplitude by 82+/-5% and almost doubled the rate of channel deactivation. The GABA(A) receptor alpha6 subunit is selectively expressed in cerebellar granule cells. Although concentrated at synapses, it is also found on extrasynaptic membranes. Using a mouse line (Deltaalpha6lacZ) lacking this subunit, we investigated its role in the somato-synaptic differences in GABA(A) receptor function. All differences between cell body and synaptic GABA(A) receptors observed in wild-type (WT) granule cells persisted in Deltaalpha6lacZ cells, thus demonstrating that they are not specifically due to the cellular distribution of the alpha6 subunit. However, mIPSCs from WT and Deltaalpha6lacZ cells differed in both their kinetics (faster decay in WT cells) and underlying single channel conductance (32 pS WT, 25 pS Deltaalpha6lacZ). This provides good evidence for a functional contribution of the alpha6 subunit to postsynaptic GABA(A) receptors in these cells. Despite this, deactivation kinetics of mIPSCs in WT and Deltaalpha6lacZ granule cells exhibited similar benzodiazepene (BDZ) sensitivity. This suggests that the enhanced BDZ-induced ataxia seen in Deltaalpha6lacZ mice may reflect physiological activity at extrasynaptic receptors which, unlike those at synapses, display differential BDZ-sensitivity in WT and Deltaalpha6lacZ granule cells (Jones, A.M., Korpi, E.R., McKernan, R.M., Nusser, Z., Pelz, R., Makela, R., Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J.H., Wisden
Paterlini M, Revilla V, Grant AL, et al., 2000, Expression of the neuronal calcium sensor protein family in the rat brain, Neuroscience, Vol: 99, Pages: 205-216, ISSN: 0306-4522
The neuronal calcium sensor proteins are members of the calcium-binding protein superfamily. They control localized calcium signalling on membranes and may make G-protein cascades sensitive to cytosolic calcium. The family members are recoverin (visinin, S-modulin), neuronal calcium sensor-1 (frequenin), hippocalcin, neuronal visinin-like protein-1 (visinin-like protein, neurocalcin-alpha), neuronal visinin-like protein-2 and neuronal visinin-like protein-3. Recoverin is expressed only in the retina and pineal gland. Using in situ hybridization, we mapped the expression of the other neuronal calcium sensor protein genes in the adult rat brain. Neuronal visinin-like protein-1 messenger RNA has a widespread distribution and is abundant in all brain areas except the caudate-putamen. Neuronal calcium sensor-1 gene expression is pan-neuronal. Neuronal calcium sensor-1 messenger RNA is present in the dendrites of hippocampal pyramidal and granule cells, suggesting a specific role in dendritic function. Hippocalcin and neuronal visinin-like protein-2 are mainly expressed in the forebrain and have similar expression patterns (neocortex, hippocampus and caudate-putamen). Neuronal visinin-like protein-3 has the most restricted expression; its highest expression level is in the cerebellum (Purkinje and granule cells). However, the neuronal visinin-like protein-3 gene is also expressed in many ventral nuclei throughout the fore- and midbrain, in the medial habenulae, and in the superior and inferior colliculi. The neuronal calcium sensor proteins are a relatively unexplored family of Ca(2+)-binding proteins. They are likely to be involved in many diverse areas of neuronal signalling. In this paper, we describe their expression in the rat brain as determined by in situ hybridization. As all five neuronal calcium sensor protein genes have distinctive expression patterns, they probably perform specific functions.
Uusi-Oukari M, Heikkila J, Sinkkonen ST, et al., 2000, Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABA(A) receptor beta2-alpha6-alpha1-gamma2 subunit gene cluster, Mol Cell Neurosci, Vol: 16, Pages: 34-41, ISSN: 1044-7431
Clustering of GABA(A) receptor alpha1, alpha6, beta2, and gamma2 subunit genes on mouse chromosome 11/human chromosome 5 may have functional significance for coordinating expression patterns, but until now there has been no evidence for cross-talk between the genes. However, altering the structure of the alpha6 gene, specifically expressed in the cerebellum, with neomycin gene insertions in two different experiments unexpectedly reduced the expression of the widespread alpha1 and beta2 genes in the forebrain. There were corresponding reductions in the levels of alpha1 and beta2 subunit proteins and in autoradiographic ligand binding densities to GABA(A) receptors in the forebrain of alpha6-/- mice. The gamma2 mRNA level was not changed, nor were beta3 and delta mRNAs. The data suggest that elements in the neo gene may have an influence over long distances in the GABA(A) subunit gene complex on as yet undefined structures coordinating the expression of the alpha1 and beta2 genes
Wisden W, 1999, Why so many GABA(A) receptor subtypes? Clues from cerebellar granule cells., Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S54-S54, ISSN: 0022-3042
Korpi ER, Koikkalainen P, Vekovischeva OY, et al., 1999, Cerebellar granule-cell-specific GABA-A receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice, Eur J Neurosci, Vol: 11, Pages: 233-240, ISSN: 0953-816X
Benzodiazepine- and alcohol-induced ataxias in rodents have been proposed to be affected by the gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which contributes to receptors specifically expressed in cerebellar granule cells. We have studied an alpha 6 -/- mouse line for motor performance and drug sensitivity. These mice, as a result of a specific genetic lesion, carry a precise impairment at their Golgi-granule cell synapses. On motor performance tests (rotarod, horizontal wire, pole descending, staircase and swimming tests) there were no robust baseline differences in motor function or motor learning between alpha 6 -/- and alpha 6 +/+ mice. On the rotarod test, however, the mutant mice were significantly more impaired by diazepam (5-20 mg/kg, i.p.), when compared with alpha 6 +/+ control and background C57BL/6J and 129/SvJ mouse lines. Ethanol (2.0-2.5 g/kg, i.p.) produced similar impairment in the alpha 6 -/- and alpha +/+ mice. Diazepam-induced ataxia in alpha 6 -/- mice could be reversed by the benzodiazepine site antagonist flumazenil, indicating the involvement of the remaining alpha 1 beta 2/3 gamma 2 GABAA receptors of the granule cells. The level of activity in this synapse is crucial in regulating the execution of motor tasks. We conclude that GABAA receptor alpha 6 subunit-dependent actions in the cerebellar cortex can be compensated by other receptor subtypes; but if not for the alpha 6 subunit, patients on benzodiazepine medication would suffer considerably from ataxic side-effects.
Wisden W, Stephens DN, 1999, Towards better benzodiazepines, Nature, Vol: 401, Pages: 751-752, ISSN: 0028-0836
Makela R, Wisden W, Korpi ER, 1999, Loreclezole and La3+ differentiate cerebellar granule cell GABA(A) receptor subtypes, Eur J Pharmacol, Vol: 367, Pages: 101-105, ISSN: 0014-2999
The effects of loreclezole and La3+ on native cerebellar GABA(A) receptors were compared between GABA(A) receptor alpha6 subunit-deficient (alpha6-/-) and wildtype mouse lines, produced through homologous recombination, using t-[35S]butylbicyclophosphorothionate ([35S]TBPS) autoradiography in brain sections. In the alpha6 subunit-deficient mice, the GABA receptor antagonistic ability of La3+ was abolished in the cerebellar granule cell layer, consistent with its opposite actions on alpha6- and of alpha1 subunit-containing receptors. La3+ significantly potentiated the action of GABA in the molecular layer of the alpha6-/- mice, but not in that of the wildtype mice. The potentiation of agonistic GABA inhibition of [35S]TBPS binding by loreclezole in alpha6-/- granule cells was reduced, suggesting an emergence of low-affinity GABA(A) receptors. The present results thus identified two ligands that may be useful in studying functional roles of cerebellar alpha1 and alpha6 subunit-containing GABA(A) receptor subtypes.
Bahn S, Wisden W, Dunnett SB, et al., 1999, The intrinsic specification of gamma-aminobutyric acid type A receptor alpha6 subunit gene expression in cerebellar granule cells, Eur J Neurosci, Vol: 11, Pages: 2194-2198, ISSN: 0953-816X
The patterns of gamma-aminobutyric acid type A (GABAA) receptor subunit gene expression in the brain are complex. For example, mouse hippocampal dentate granule cells express many subunit genes, whereas adult cerebellar granule cells, which may share differentiation mechanisms, have a smaller compliment and uniquely express the alpha6 subunit gene. To see how the alpha6 expression component arises, i.e. if intrinsically or environmentally specified, we used a mouse line (Deltaalpha6lacZ) with a beta-galactosidase reporter inserted into the alpha6 gene. Precursor cells from postnatal day 1 Deltaalpha6lacZ cerebellum were transplanted to the adult hippocampus and cerebellum of wild-type mice; 4 weeks after transplantation, Deltaalpha6lacZ cells expressed alpha6-lacZ in the hippocampus, amygdala and cerebellum. Thus, different adult environments support both the development and maintenance of alpha6 gene expression from cerebellar granule cell precursors. Establishing alpha6 gene expression is not likely to require specific patterns of neurotransmitter innervation or other factors present only in the developing brain; instead, alpha6 expression can be timed and maintained autonomously.
Nusser Z, Ahmad Z, Tretter V, et al., 1999, Alterations in the expression of GABA-A receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene, Eur J Neurosci, Vol: 11, Pages: 1685-1697, ISSN: 0953-816X
Any given subunit of the heteromultimeric type-A gamma-aminobutyric acid (GABA) GABAA receptor may be present in several receptor subtypes expressed by individual neurons. Changes in the expression of a subunit may result in differential changes in the expression of other subunits depending on the subunit composition of the receptor subtype, leading to alterations in neuronal responsiveness to GABA. We used the targeted disruption of the alpha6 subunit gene to test for changes in the expression of other GABAA receptor subunits. Immunoprecipitation and ligand binding experiments indicated that GABAA receptors were reduced by approximately 50% in the cerebellum of alpha6 -/- mice. Western blot experiments indicated that the alpha6 subunit protein completely disappeared from the cerebellum of alpha6 -/- mice, which resulted in the disappearance of the delta subunit from the plasma membrane of granule cells. The amount of beta2, beta3 and gamma2 subunits was reduced by approximately 50%, 20% and 40%, respectively, in the cerebella of alpha6 -/- mice. A comparison of the reduction in the level of alpha1, beta2, beta3, gamma2, or delta-subunit-containing receptors in alpha6 -/- cerebellum with those observed after removal of alpha6-subunit-containing receptors from the cerebella of alpha6 +/+ mice by immuno-affinity chromatography demonstrated the presence of a significantly higher than expected proportion of receptors containing beta3 subunits in alpha6 -/- mice. The receptors containing alpha1, beta2, beta3 and gamma2 subunits were present in the plasma membrane of granule cells of alpha6 -/- mice at both synaptic and extrasynaptic sites, as shown by electron microscopic immunocytochemistry. Despite the changes, the alpha1 subunit content of Golgi-cell-to-granule-cell synapses in alpha6 -/- animals remained unaltered, as did the frequency of alpha1 immunopositive synapses in the glomeruli. Furthermore, no change was apparent in the expression of the alpha1, beta2 and ga
Emson CL, Bell SE, Jones A, et al., 1998, Interleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 188, Pages: 399-404, ISSN: 0022-1007
Emson CL, Bell SE, Jones A, et al., 1998, nterleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13, J Exp Med, Vol: 188, Pages: 399-404, ISSN: 0022-1007
Recent studies using interleukin (IL)-4-deficient animals have highlighted the existence of IL-4-independent immunoglobulin (Ig)E induction. We have established transgenic mice expressing IL-13 from a transgene comprising a genomic fragment containing the IL-13 gene and the human CD2 locus control region. The transgenes were expressed in lymphoid tissues and induced by T cell activators, suggesting regulation by elements of the IL-13 promoter. IL-13 transgenic lines expressed 10-100-fold higher levels of serum IgE than their littermate controls, but had normal levels of other serum Ig isotypes. Elevated IgE levels were also detected in sera from IL-4-deficient mice carrying IL-13 transgenes, indicating that IL-4 is not required for IL-13-induced IgE expression in the mouse. Expression of IL-13 also perturbed the development of thymocytes. Although thymocyte development was normal up to 4 wk of age, thymocyte number decreased dramatically thereafter, reaching 10% of normal by 10 wk, and despite normal size and appearance, histological examination demonstrated that transgenic thymi contained only small foci of thymocytes. The reduction in thymocyte number was due mainly to a depletion of CD4(+)CD8(+) thymocytes, and did not affect significantly the composition of peripheral T cell populations. These data indicate that expression of IL-13 transgenes in vivo can regulate IgE production in the mouse, and that IL-13 may also influence thymocyte development.
Mellor JR, Merlo D, Jones A, et al., 1998, Mouse cerebellar granule cell differentiation: electrical activity regulates the GABA-A receptor alpha 6 subunit gene, J Neurosci, Vol: 18, Pages: 2822-2833, ISSN: 0270-6474
GABAA receptor alpha6 subunit gene expression marks cerebellar granule cell maturation. To study this process, we used the Deltaalpha6lacZ mouse line, which has a lacZ reporter inserted into the alpha6 gene. At early stages of postnatal cerebellar development, alpha6-lacZ expression is mosaic; expression starts at postnatal day 5 in lobules 9 and 10, and alpha6-lacZ is switched on inside-out, appearing first in the deepest postmigratory granule cells. We looked for factors regulating this expression in cell culture. Membrane depolarization correlates inversely with alpha6-lacZ expression: granule cells grown in 25 mM [K+]o for 11-15 d do not express the alpha6 gene, whereas cultures grown for the same period in 5 mM [K+]o do. This is influenced by a critical early period: culturing for >/=3 d in 25 mM [K+]o curtails the ability to induce the alpha6 gene on transfer to 5 mM [K+]o. If the cells start in 5 mM [K+]o, however, they still express the alpha6-lacZ gene in 25 mM [K+]o. In contrast to granule cells grown in 5 mM [K+]o, cells cultured in 25 mM [K+]o exhibit no action potentials, mEPSCs, or mIPSCs. In chronic 5 mM [K+]o, factors may therefore be released that induce alpha6. Blockade of ionotropic and metabotropic GABA and glutamate receptors or L-, N-, and P/Q-type Ca2+ channels did not prevent alpha6-lacZ expression, but inhibition of action potentials with tetrodotoxin blocked expression in a subpopulation of cells.
Mellor JR, Jones A, Wisden W, et al., 1997, Effects of culture conditions on the expression of the GABA(A) receptor alpha 6 subunit gene in cerebellar granule cells in vitro., Publisher: CAMBRIDGE UNIV PRESS, Pages: P178-P178, ISSN: 0022-3751
Korpi ER, Mattila M, Wisden W, et al., 1997, GABA(A)-receptor subtypes: Clinical efficacy and selectivity of benzodiazepine site ligands (vol 29, pg 275, 1997), ANNALS OF MEDICINE, Vol: 29, Pages: 468-468, ISSN: 0785-3890
Korpi ER, Wisden W, Lüddens H, 1997, [Better cure for anxiety, sleep disorders, epilepsy?]., Lakartidningen, Vol: 94, Pages: 3403-3408, ISSN: 0023-7205
Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter, is characterised by rapid effects that are mediated via GABAA, receptors. These receptors are also targets for many drugs including benzodiazepines, barbiturates and general anaesthetics. Recognition of the heterogeneity of GABAA receptors has opened up new possibilities for the development of more selective therapeutic agents. In particular, subtype-specific receptor ligands varying in intrinsic activity are likely to give rise to fewer side effects than do currently available drugs.
Korpi ER, Wisden W, Lüddens H, 1997, Improved remedies for anxiety, sleeping disorders and epilepsy?, Lakartidningen, Pages: 3403-3408, ISSN: 0023-7205
Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter, is characterised by rapid effects that are mediated via GABAA receptors. These receptors are also targets for many drugs including benzodiazepines, barbiturates and general anaesthetics. Recognition of the heterogeneity of GABAA receptors has opened up new possibilities for the development of more selective therapeutic agents. In particular, subtype-specific receptor ligands varying in intrinsic activity are likely to give rise to fewer side effects than do currently available drugs.
Korpi ER, Mattila M, Wisden W, et al., 1997, Correction: Clinical Efficacy and Selectivity of Benzodiazepine Site Ligands (Annals of Medicine (1997) 29 (275-282)), Annals of Medicine, Vol: 29, ISSN: 0785-3890
Wisden W, Moss SJ, 1997, γ-Aminobutyric acid type a receptor subunit assembly sorting: Gene targeting and cell biology approaches, Biochemical Society Transactions, Vol: 25, Pages: 820-824, ISSN: 0300-5127
Wisden W, 1997, Ligand-gated ion channel subunit partnerships: GABA<inf>A</inf> receptor α<inf>6</inf> subunit gene inactivation inhibits δ subunit expression, Biochemical Society Transactions, Vol: 25, ISSN: 0300-5127
Cerebellar granule cells express six GABAA receptor subunits abundantly (α1, α6, β2, β3, γ2 and δ), and assemble a variety of pentameric receptor subtypes, with unknown subunit compositions. However, the rules guiding receptor subunit assembly are unclear. Removal of intact α6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied (Jones et al., 1997). Exon 8 of the mouse α6 -/- subunit gene was disrupted by homologous recombination. In α6 -1- granule cells, the δ subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with δ subunit-specific antibodies. The δ subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the δ subunit. These results provide genetic evidence for a specific association between the α6 and δ subunits.
Grant AL, Wisden W, 1997, Neuron-specific gene expression., Molecular biology of the neuron, Editors: Davies, Morris, Publisher: Oxford University Press, USA, Pages: 67-93, ISBN: 9781859962404
A valuable compendium of comprehensive and up-to-date reviews of neuronal molecularbiology by leading researchers in the field, this book focuses on genetic ...
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