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1.
J Neurosci ; 26(47): 12339-50, 2006 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-17122059

RESUMO

Fibroblast growth factor receptors (Fgfr) comprise a widely expressed family of developmental regulators implicated in oligodendrocyte (OL) maturation of the CNS. Fgfr2 is expressed by OLs in myelinated fiber tracks. In vitro, Fgfr2 is highly upregulated during OL terminal differentiation, and its activation leads to enhanced growth of OL processes and the formation of myelin-like membranes. To investigate the in vivo function of Fgfr2 signaling by myelinating glial cells, we inactivated the floxed Fgfr2 gene in mice that coexpress Cre recombinase (cre) as a knock-in gene into the OL-specific 2',3'-cyclic nucleotide phosphodiesterase (Cnp1) locus. Surprisingly, no obvious defects were detected in brain development of these conditional mutants, including the number of OLs, the onset and extent of myelination, the ultrastructure of myelin, and the expression level of myelin proteins. However, unexpectedly, a subset of these conditional Fgfr2 knock-out mice that are homozygous for cre and therefore are also Cnp1 null, displayed a dramatic hyperactive behavior starting at approximately 2 weeks of age. This hyperactivity was abolished by treatment with dopamine receptor antagonists or catecholamine biosynthesis inhibitors, suggesting that the symptoms involve a dysregulation of the dopaminergic system. Although the molecular mechanisms are presently unknown, this novel mouse model of hyperactivity demonstrates the potential involvement of OLs in neuropsychiatric disorders, as well as the nonpredictable role of genetic interactions in the behavioral phenotype of mice.


Assuntos
2',3'-Nucleotídeo Cíclico Fosfodiesterases/fisiologia , Fator 2 de Crescimento de Fibroblastos/fisiologia , Hipercinese/genética , Hipercinese/fisiopatologia , Oligodendroglia/metabolismo , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/deficiência , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Western Blotting/métodos , Encéfalo/citologia , Diferenciação Celular/genética , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Fator 2 de Crescimento de Fibroblastos/deficiência , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão/métodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Oligodendroglia/ultraestrutura , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Proc Natl Acad Sci U S A ; 98(23): 13373-8, 2001 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-11698689

RESUMO

Differential expression of ion channels contributes functional diversity to sensory neuron signaling. We find nerve injury induced by the Chung model of neuropathic pain leads to striking reductions in voltage-gated K(+) (Kv) channel subunit expression in dorsal root ganglia (DRG) neurons, suggesting a potential molecular mechanism for hyperexcitability of injured nerves. Moreover, specific classes of DRG neurons express distinct Kv channel subunit combinations. Importantly, Kv1.4 is the sole Kv1 alpha subunit expressed in smaller diameter neurons, suggesting that homomeric Kv1.4 channels predominate in A delta and C fibers arising from these cells. These neurons are presumably nociceptors, because they also express the VR-1 capsaicin receptor, calcitonin gene-related peptide, and/or Na(+) channel SNS/PN3/Nav1.8. In contrast, larger diameter neurons associated with mechanoreception and proprioception express high levels of Kv1.1 and Kv1.2 without Kv1.4 or other Kv1 alpha subunits, suggesting that heteromers of these subunits predominate on large, myelinated afferent axons that extend from these cells.


Assuntos
Neurônios Aferentes/fisiologia , Dor/fisiopatologia , Canais de Potássio/fisiologia , Animais , Imunofluorescência , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Masculino , Neurônios Aferentes/metabolismo , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/metabolismo
3.
Dev Biol ; 236(1): 5-16, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11456440

RESUMO

Voltage-gated Na(+) and K(+) channels are localized to distinct subcellular domains in mammalian myelinated nerve fibers. Specifically, Na(+) channels are clustered in high densities at nodes of Ranvier, while K(+) channels are found in juxtaparanodal zones just beyond regions of axoglial contact where sequential layers of the myelin sheath terminate. Specific targeting, clustering, and maintenance of these channels in their respective domains are essential to achieve high conduction velocities of action potential propagation. The cellular, molecular, and developmental mechanisms that exist to achieve this neuronal specialization are discussed and reviewed. Current evidence points to a prominent role in channel clustering played by myelinating glial cells, and sites of axoglial contact in particular.


Assuntos
Canais Iônicos , Neurônios/fisiologia , Nós Neurofibrosos/fisiologia , Animais , Camundongos , Neurônios/química , Canais de Potássio/química , Estrutura Terciária de Proteína , Nós Neurofibrosos/química , Ratos , Transdução de Sinais , Canais de Sódio/química
4.
Neuron ; 30(1): 91-104, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11343647

RESUMO

Voltage-dependent sodium channels are uniformly distributed along unmyelinated axons, but are highly concentrated at nodes of Ranvier in myelinated axons. Here, we show that this pattern is associated with differential localization of distinct sodium channel alpha subunits to the unmyelinated and myelinated zones of the same retinal ganglion cell axons. In adult axons, Na(v)1.2 is localized to the unmyelinated zone, whereas Na(v)1.6 is specifically targeted to nodes. During development, Na(v)1.2 is expressed first and becomes clustered at immature nodes of Ranvier, but as myelination proceeds, Na(v)1.6 replaces Na(v)1.2 at nodes. In Shiverer mice, which lack compact myelin, Na(v)1.2 is found throughout adult axons, whereas little Na(v)1.6 is detected. Together, these data show that sodium channel isoforms are differentially targeted to distinct domains of the same axon in a process associated with formation of compact myelin.


Assuntos
Axônios/metabolismo , Bainha de Mielina/metabolismo , Nervo Óptico/crescimento & desenvolvimento , Canais de Sódio/metabolismo , Animais , Axônios/ultraestrutura , Imuno-Histoquímica , Camundongos , Camundongos Mutantes Neurológicos/anatomia & histologia , Camundongos Mutantes Neurológicos/crescimento & desenvolvimento , Camundongos Mutantes Neurológicos/metabolismo , Bainha de Mielina/ultraestrutura , Nervo Óptico/metabolismo , Nervo Óptico/ultraestrutura , Nervos Periféricos/crescimento & desenvolvimento , Nervos Periféricos/metabolismo , Nervos Periféricos/ultraestrutura , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/ultraestrutura , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/ultraestrutura , Canais de Sódio/genética
5.
J Comp Neurol ; 429(1): 166-76, 2001 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11086297

RESUMO

Axonal K+ channels involved in normal spinal cord function are candidate targets for therapeutics, which improve sensorimotor function in spinal cord injury. To this end, we have investigated the expression, localization, and coassociation of Kv1 alpha and beta subunits in human, rat, and bovine spinal cord. We find that Kv1.1, Kv1.2, and Kvbeta2 form heteromultimeric complexes at juxtaparanodal zones in myelinated fibers. However, these same complexes are also present in paranodal regions of some spinal cord axons, and staining with antibodies against Caspr, a component of the paranodal axoglial junction, overlaps with these paranodal K+ channels. This latter observation suggests a unique role for these channels in normal spinal cord function and may provide an explanation for the sensitivity of spinal cord to K+ channel blockers. Moreover, the conservation of these characteristics between human, rat, and bovine nodes of Ranvier suggests an essential role for this defined channel complex in spinal cord function.


Assuntos
Fibras Nervosas Mielinizadas/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Nós Neurofibrosos/metabolismo , Medula Espinal/metabolismo , Animais , Bovinos , Humanos , Canal de Potássio Kv1.1 , Canal de Potássio Kv1.2 , Fibras Nervosas Mielinizadas/ultraestrutura , Canais de Potássio/química , Nós Neurofibrosos/ultraestrutura , Ratos , Medula Espinal/citologia
6.
J Physiol ; 525 Pt 1: 63-73, 2000 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-10811725

RESUMO

Na+ and K+ channel localization and clustering are essential for proper electrical signal generation and transmission in CNS myelinated nerve fibres. In particular, Na+ channels are clustered at high density at nodes of Ranvier, and Shaker-type K+ channels are sequestered in juxtaparanodal zones, just beyond the paranodal axoglial junctions. The mechanisms of channel localization at nodes of Ranvier in the CNS during development in both normal and hypomyelinating mutant animals are discussed and reviewed. As myelination proceeds, Na+ channels are initially found in broad zones within gaps between neighbouring oligodendroglial processes, and then are condensed into focal clusters. This process appears to depend on the formation of axoglial junctions. K+ channels are first detected in juxtaparanodal zones, and in mutant mice lacking normal axoglial junctions, these channels fail to cluster. In these mice, despite the presence of numerous oligodendrocytes, Na+ channel clusters are rare, and when present, are highly irregular. A number of molecules have recently been described that are candidates for a role in the neuron-glial interactions driving ion channel clustering. This paper reviews the cellular and molecular events responsible for formation of the mature node of Ranvier in the CNS.


Assuntos
Sistema Nervoso Central/metabolismo , Canais Iônicos/metabolismo , Nervo Óptico/metabolismo , Potenciais de Ação , Animais , Sistema Nervoso Central/embriologia , Imunofluorescência , Nervo Óptico/citologia , Canais de Potássio/metabolismo , Ratos , Canais de Sódio/metabolismo
7.
J Neurosci ; 19(17): 7516-28, 1999 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-10460258

RESUMO

Na(+) channel clustering at nodes of Ranvier in the developing rat optic nerve was analyzed to determine mechanisms of localization, including the possible requirement for glial contact in vivo. Immunofluorescence labeling for myelin-associated glycoprotein and for the protein Caspr, a component of axoglial junctions, indicated that oligodendrocytes were present, and paranodal structures formed, as early as postnatal day 7 (P7). However, the first Na(+) channel clusters were not seen until P9. Most of these were broad, and all were excluded from paranodal regions of axoglial contact. The number of detected Na(+) channel clusters increased rapidly from P12 to P22. During this same period, conduction velocity increased sharply, and Na(+) channel clusters became much more focal. To test further whether oligodendrocyte contact directly influences Na(+) channel distributions, nodes of Ranvier in the hypomyelinating mouse Shiverer were examined. This mutant has oligodendrocyte-ensheathed axons but lacks compact myelin and normal axoglial junctions. During development Na(+) channel clusters in Shiverer mice were reduced in numbers and were in aberrant locations. The subcellular location of Caspr was disrupted, and nerve conduction properties remained immature. These results indicate that in vivo, Na(+) channel clustering at nodes depends not only on the presence of oligodendrocytes but also on specific axoglial contact at paranodal junctions. In rats, ankyrin-3/G, a cytoskeletal protein implicated in Na(+) channel clustering, was detected before Na(+) channel immunoreactivity but extended into paranodes in non-nodal distributions. In Shiverer, ankyrin-3/G labeling was abnormal, suggesting that its localization also depends on axoglial contact.


Assuntos
Envelhecimento/fisiologia , Axônios/fisiologia , Moléculas de Adesão Celular Neuronais , Regulação da Expressão Gênica no Desenvolvimento , Neuroglia/fisiologia , Oligodendroglia/fisiologia , Nervo Óptico/fisiologia , Nós Neurofibrosos/fisiologia , Canais de Sódio/fisiologia , Potenciais de Ação/fisiologia , Sequência de Aminoácidos , Animais , Comunicação Celular , Epitopos/química , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C3H , Camundongos Mutantes Neurológicos , Dados de Sequência Molecular , Bainha de Mielina/fisiologia , Condução Nervosa , Nervo Óptico/crescimento & desenvolvimento , Ratos , Receptores de Superfície Celular/análise , Canais de Sódio/análise , Canais de Sódio/genética
8.
J Neurosci ; 19(11): 4245-62, 1999 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-10341229

RESUMO

Tenascin-R (TN-R), an extracellular matrix glycoprotein of the CNS, localizes to nodes of Ranvier and perineuronal nets and interacts in vitro with other extracellular matrix components and recognition molecules of the immunoglobulin superfamily. To characterize the functional roles of TN-R in vivo, we have generated mice deficient for TN-R by homologous recombination using embryonic stem cells. TN-R-deficient mice are viable and fertile. The anatomy of all major brain areas and the formation and structure of myelin appear normal. However, immunostaining for the chondroitin sulfate proteoglycan phosphacan, a high-affinity ligand for TN-R, is weak and diffuse in the mutant when compared with wild-type mice. Compound action potential recordings from optic nerves of mutant mice show a significant decrease in conduction velocity as compared with controls. However, at nodes of Ranvier there is no apparent change in expression and distribution of Na+ channels, which are thought to bind to TN-R via their beta2 subunit. The distribution of carbohydrate epitopes of perineuronal nets recognized by the lectin Wisteria floribunda or antibodies to the HNK-1 carbohydrate on somata and dendrites of cortical and hippocampal interneurons is abnormal. These observations indicate an essential role for TN-R in the formation of perineuronal nets and in normal conduction velocity of optic nerve.


Assuntos
Axônios/fisiologia , Sistema Nervoso Central/fisiopatologia , Proteínas da Matriz Extracelular/deficiência , Proteínas do Tecido Nervoso/deficiência , Condução Nervosa/fisiologia , Tenascina/deficiência , Animais , Células Cultivadas , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Glicoproteína Associada a Mielina/fisiologia , Rede Nervosa/fisiologia , Proteínas do Tecido Nervoso/análise , Nervo Óptico/ultraestrutura , Nós Neurofibrosos/fisiologia , Células-Tronco/fisiologia
9.
J Neurocytol ; 28(4-5): 319-31, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10739574

RESUMO

The localization of Shaker-type K(+) channels in specialized domains of myelinated central nervous system axons was studied during development of the optic nerve. In adult rats Kv1.1, Kv1.2, Kv1.6, and the cytoplasmic beta-subunit Kvbeta2 were colocalized in juxtaparanodal zones. During development, clustering of K(+) channels lagged behind that for nodal Na(+) channels by about 5 days. In contrast to the PNS, K(+) channels were initially expressed fully segregated from nodes and paranodes, the latter identified by immunofluorescence of Caspr, a component of axoglial junctions. Clusters of K(+) channels were first detected at postnatal day 14 (P14) at a limited number of sites. Expression increased until all juxtaparanodes had immunoreactivity by P40. Developmental studies in hypomyelinating Shiverer mice revealed dramatically disrupted axoglial junctions, aberrant Na(+) channel clusters, and little or no detectable clustering of K(+) channels at all ages. These results suggest that in the optic nerve, compact myelin and normal axoglial junctions are essential for proper K(+) channel clustering and localization.


Assuntos
Axônios/metabolismo , Bainha de Mielina/metabolismo , Nervo Óptico/citologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Potenciais de Ação/fisiologia , Fatores Etários , Animais , Axônios/química , Canais de Potássio de Retificação Tardia , Eletrofisiologia , Imunofluorescência , Canal de Potássio Kv1.1 , Canal de Potássio Kv1.2 , Camundongos , Camundongos Endogâmicos C3H , Camundongos Mutantes Neurológicos , Mutação , Bainha de Mielina/patologia , Neuroglia/citologia , Nervo Óptico/crescimento & desenvolvimento , Nervo Óptico/patologia , Canais de Potássio/análise , Canais de Potássio/genética , Coelhos , Nós Neurofibrosos/química , Nós Neurofibrosos/metabolismo , Ratos , Ratos Endogâmicos Lew , Superfamília Shaker de Canais de Potássio
10.
J Neurophysiol ; 79(2): 529-36, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9463419

RESUMO

Conduction in rat peripheral nerve has been monitored following the stimulated release of nitric oxide (NO) from diethylamine-NONOate (DEA-NONOate). Branches of the sciatic nerve were dissected, but left otherwise intact, and propagating signals recorded externally. At levels consistent with inflammation, NO exposure resulted in a complete loss of the compound action potential. Conduction was fully restored on removal of the drug. Most notably, this loss of excitability was dependent on the axonal environment. Removal of the connective tissue sheaths surrounding the nerve bundle, a process that normally enhances drug action, prevented block of signal propagation by nitric oxide. The epineurium seemed not to be required, and the decreased susceptibility to NO appeared to be correlated with a gradual loss of a component of the endoneurium that surrounds individual fibers. Tested on the rat vagus nerve, NO eliminated action potentials in both myelinated and unmyelinated fibers. One chemical mechanism that is consistent with the reversibility of block and the observed lack of effect of 8-Br-cGMP on conduction is the formation of a nitrosothiol through reaction of NO with a sulfhydryl group. In contrast to DEA-NONOate, S-nitrosocysteine, which can both transfer nitrosonium cation (NO+) to another thiol and also release nitric oxide, was effective on both intact and desheathed preparations. It has previously been demonstrated that chemical modification of invertebrate axons by sulfhydryl-reactive compounds induces a slow inactivation of Na+ channels. Nitric oxide block of axonal conduction may contribute to clinical deficits in inflammatory diseases of the nervous system.


Assuntos
Axônios/fisiologia , Bainha de Mielina/fisiologia , Condução Nervosa/efeitos dos fármacos , Óxido Nítrico/farmacologia , S-Nitrosotióis , Potenciais de Ação/efeitos dos fármacos , Animais , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Cisteína/análogos & derivados , Cisteína/farmacologia , Depressão Química , Feminino , Hidrazinas/farmacologia , Óxidos de Nitrogênio , Compostos Nitrosos/farmacologia , Oxirredução , Ratos , Ratos Endogâmicos Lew , Nervo Isquiático/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia , Tetrodotoxina/farmacologia , Nervo Vago/efeitos dos fármacos
11.
J Neurosci ; 18(1): 36-47, 1998 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9412484

RESUMO

The K+ channel alpha-subunits Kv1.1 and Kv1.2 and the cytoplasmic beta-subunit Kvbeta2 were detected by immunofluorescence microscopy and found to be colocalized at juxtaparanodes in normal adult rat sciatic nerve. After demyelination by intraneural injection of lysolecithin, and during remyelination, the subcellular distributions of Kv1.1, Kv1.2, and Kvbeta2 were reorganized. At 6 d postinjection (dpi), axons were stripped of myelin, and K+ channels were found to be dispersed across zones that extended into both nodal and internodal regions; a few days later they were undetectable. By 10 dpi, remyelination was underway, but Kv1.1 immunoreactivity was absent at newly forming nodes of Ranvier. By 14 dpi, K+ channels were detected but were in the nodal gap between Schwann cells. By 19 dpi, most new nodes had Kv1.1, Kv1.2, and Kvbeta2, which precisely colocalized. However, this nodal distribution was transient. By 24 dpi, the majority of K+ channels was clustered within paranodal regions of remyelinated axons, leaving a gap that overlapped with Na+ channel immunoreactivity. Inhibition of Schwann cell proliferation delayed both remyelination and the development of the K+ channel distributions described. Conduction studies indicate that neither 4-aminopyridine (4-AP) nor tetraethylammonium alters normal nerve conduction. However, during remyelination, 4-AP profoundly increased both compound action potential amplitude and duration. The level of this effect matched closely the nodal presence of these voltage-dependent K+ channels. Our results suggest that K+ channels may have a significant effect on conduction during remyelination and that Schwann cells are important in K+ channel redistribution and clustering.


Assuntos
Bainha de Mielina/química , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/análise , Canais de Potássio/metabolismo , 4-Aminopiridina/farmacologia , Potenciais de Ação/fisiologia , Animais , Axônios/química , Axônios/efeitos dos fármacos , Axônios/fisiologia , Doenças Desmielinizantes , Condutividade Elétrica , Eletrofisiologia , Feminino , Canal de Potássio Kv1.1 , Mitomicina/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Bloqueadores dos Canais de Potássio , Nós Neurofibrosos/química , Nós Neurofibrosos/metabolismo , Ratos , Ratos Endogâmicos Lew , Células de Schwann/metabolismo , Nervo Isquiático/química , Nervo Isquiático/citologia , Nervo Isquiático/ultraestrutura , Tetraetilamônio/farmacologia
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