RESUMO
A wealth of indirect data suggest that the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate (S1P) receptor plays important roles in development. In vitro, it activates several forms of development-related signal transduction and regulates cellular proliferation, differentiation and survival. It is expressed during embryogenesis, and mutation of an H218-like gene in zebrafish leads to profound defects in embryonic development. Nevertheless, the in vivo functions served by H218 signalling have not been directly investigated. We report here that mice in which the H218 gene has been disrupted are unexpectedly born with no apparent anatomical or physiological defects. In addition, no abnormalities were observed in general neurological development, peripheral axon growth or brain structure. However, between 3 and 7 weeks of age, H218(-/-) mice have seizures which are spontaneous, sporadic and occasionally lethal. Electroencephalographic abnormalities were identified both during and between the seizures. At a cellular level, whole-cell patch-clamp recordings revealed that the loss of H218 leads to a large increase in the excitability of neocortical pyramidal neurons. Therefore, H218 plays an essential, unanticipated and functionally important role in the proper development and/or mediation of neuronal excitability.
Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Epilepsia/congênito , Células Piramidais/metabolismo , Receptores de Superfície Celular/deficiência , Receptores Acoplados a Proteínas G , Transdução de Sinais/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Axônios/metabolismo , Axônios/patologia , Bicuculina/farmacologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Eletroencefalografia/efeitos dos fármacos , Epilepsia/genética , Epilepsia/fisiopatologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Antagonistas GABAérgicos/farmacologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Knockout/genética , Camundongos Knockout/crescimento & desenvolvimento , Camundongos Knockout/metabolismo , Camundongos Mutantes Neurológicos/genética , Camundongos Mutantes Neurológicos/crescimento & desenvolvimento , Camundongos Mutantes Neurológicos/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Exame Neurológico , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores de Lisofosfolipídeos , Convulsões/congênito , Convulsões/genética , Convulsões/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Administration of nerve growth factor (NGF) by intracerebroventricular infusion or transplantation of NGF-secreting cells to the basal forebrain improves spatial memory in aged animals. Using the adeno-associated virus (AAV) vector system, basal forebrain neurons were transduced to produce NGF ectopically for long intervals (at least 9 months). Rats received intraseptal injections of either the control vector, pTR-UF4, or the pTR-NGFmyc at 3 months of age, prior to testing their performance in the Morris water task. An age-related decrease in the acquisition of the hidden platform location was found at 12 months of age in the pTR-UF4 control group, but not in the pTR-NGFmyc group. Further, when compared to 3 month old untreated animals, the control group, but not the pTR-NGFmyc group, was impaired at 12 months of age. Concomitant to preventing age-related memory deficits, the NGF gene transfer increased cholinergic neuron size by 34% in the medial septum. This approach may therefore represent a viable therapy for age-related dementia involving dysfunction in cholinergic activity and memory, such as Alzheimer's disease.
