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1.
J Comp Neurol ; 523(5): 814-30, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25421039

RESUMO

The ß1 subunit of voltage-gated sodium channels, Nav ß1, plays multiple roles in neurons spanning electrophysiological modulation of sodium channel α subunits to cell adhesion and neurite outgrowth. This study used immunohistochemistry to investigate Nav ß1 subneuronal and regional expression. Nav ß1 was enriched at axon initial segments (AIS) and nodes of Ranvier. Nav ß1 expression at the AIS was detected throughout the brain, predominantly in the hippocampus, cortex, and cerebellum. Despite expression of Nav ß1 in both excitatory and inhibitory AIS, it displayed a marked and fine-grained heterogeneity of expression. Such heterogeneity could have important implications for the tuning of single neuronal and regional excitability, especially in view of the fact that Nav ß1 coexpressed with Nav 1.1, Nav 1.2, and Nav 1.6 subunits. The disruption of Nav ß1 AIS expression by a human epilepsy-causing C121W genetic mutation in Nav ß1 was also investigated using a mouse model. AIS expression of Nav ß1 was reduced by approximately 50% in mice heterozygous for the C121W mutation and was abolished in homozygotes, suggesting that loss of Nav α subunit modulation by Nav ß1 contributes to the mechanism of epileptogenesis in these animals as well as in patients.


Assuntos
Axônios/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo , Alcenos , Animais , Western Blotting , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Imuno-Histoquímica , Interneurônios/citologia , Interneurônios/metabolismo , Interneurônios/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Mutação , Piperidinas , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
2.
Epilepsy Res ; 105(3): 272-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23602553

RESUMO

A novel form of neuronal plasticity, occurring at the axon initial segment (AIS), has recently been described. Lengthening of the AIS and movement away from the soma are consequences of changes in neuronal input and result in alterations in neuronal excitability. We hypothesised that AIS plasticity may play a role in epilepsy, due to chronic changes in neuronal activity. Immunohistochemistry and confocal microscopy were used to analyse AIS length and position in pyramidal neurons in deep layer 5 of the somatosensory cortex from 5 mice with genetic epilepsy and 4 controls, and from 3 rats subjected to amygdala kindling and 3 controls. The effect of a subtle alteration of AIS position was modelled computationally. We identified a difference in the position of the AIS in animals with seizures: in mice the AIS was positioned 0.2 µm further away from the soma, and in rats the AIS was positioned 0.6 µm closer to the soma compared with controls. Computational modelling indicated that a subtle alteration in AIS position could result in a change in action potential firing threshold. The identification of AIS plasticity in animal models of epilepsy is significant in furthering our understanding of the pathophysiological mechanisms involved in this disorder.


Assuntos
Axônios/patologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/patologia , Plasticidade Neuronal/fisiologia , Córtex Somatossensorial/patologia , Animais , Simulação por Computador , Estimulação Elétrica/efeitos adversos , Eletroencefalografia , Epilepsia/etiologia , Excitação Neurológica , Masculino , Camundongos , Camundongos Transgênicos , Modelos Neurológicos , Mutação/genética , Proteínas de Transporte de Fosfato/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Canais de Sódio/metabolismo
3.
Arch Neurol ; 69(4): 474-81, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22491192

RESUMO

BACKGROUND: Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. OBJECTIVES: To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus. DESIGN: Observational family study. SETTING: The study was coordinated in a tertiary academic hospital, with data acquired in diverse primary, secondary, and tertiary care settings. PARTICIPANTS: Consenting members of a single large family. RESULTS: A 6-generation FAME kindred of European descent was ascertained in New Zealand and Australia. Affected family members (N = 55) had fine hand tremor, with onset typically in adolescence (median age, 15 years; age range, 4-60 years). Proximal myoclonus was present in 44 of 55 (80%), arising later than hand tremor (median age, 17 years; age range, 5-60 years). Generalized tonic-clonic seizures occurred in 8 of 55 (15%), with a median age at onset of 43.5 years (age range, 18-76 years). Neurophysiological testing confirmed features of cortical reflex myoclonus. Genetic mapping narrows the FAME2 (OMIM 607876) locus on chromosome 2 to a 13.3-megabase interval, harboring 99 known protein-coding genes. CONCLUSIONS: The most common FAME phenotype in this large family is mild postural hand tremor resembling essential tremor, combined with subtle proximal myoclonus. Generalized tonic-clonic seizures are uncommon and occur around sleep onset following severe generalized myoclonus.


Assuntos
Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Saúde da Família , Ligação Genética , Transtornos da Memória/etiologia , Reconhecimento Psicológico/fisiologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 2 , Eletroencefalografia , Eletromiografia , Potenciais Somatossensoriais Evocados/genética , Feminino , Humanos , Itália , Masculino , Transtornos da Memória/genética , Pessoa de Meia-Idade , Fenótipo , Reflexo/genética , Tremor/etiologia , Tremor/genética , Adulto Jovem
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