RESUMO
Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1(+/-) mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (Assuntos
Anticonvulsivantes/farmacologia
, Epilepsia/tratamento farmacológico
, Pirazóis/farmacologia
, Quinolonas/farmacologia
, Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
, Serina-Treonina Quinases TOR/genética
, Esclerose Tuberosa/tratamento farmacológico
, Proteínas Supressoras de Tumor/genética
, Potenciais de Ação/efeitos dos fármacos
, Animais
, Modelos Animais de Doenças
, Eletroencefalografia
, Epilepsia/genética
, Epilepsia/metabolismo
, Epilepsia/patologia
, Regulação da Expressão Gênica
, Heterozigoto
, Humanos
, Masculino
, Camundongos
, Camundongos Transgênicos
, Microtomia
, Neocórtex/efeitos dos fármacos
, Neocórtex/metabolismo
, Neocórtex/patologia
, Técnicas de Patch-Clamp
, Receptores de N-Metil-D-Aspartato/genética
, Receptores de N-Metil-D-Aspartato/metabolismo
, Transdução de Sinais
, Serina-Treonina Quinases TOR/metabolismo
, Técnicas de Cultura de Tecidos
, Esclerose Tuberosa/genética
, Esclerose Tuberosa/metabolismo
, Esclerose Tuberosa/patologia
, Proteína 1 do Complexo Esclerose Tuberosa
, Proteínas Supressoras de Tumor/deficiência
RESUMO
The modulatory effect of endogenous diadenosine polyphosphates on synaptic transmission in the rat hippocampal slices has been re-examined with a non-hydrolysable Ap4A analogue diadenosine-5',5'>>-P1,P4-[beta,gamma-methylene]tetraphosphate (AppCH2ppA). We have shown that AppCH2ppA at low micromolar concentrations induce inhibition of orthodromically evoked population spikes, without affecting of excitatory postsynaptic currents and antidromic spikes recorded in the CA1 zone of hippocampus. Such a spatially selective neuronal inhibition may influence dendritic electrogenesis in pyramidal neurons and consequently mediate control of neuronal network activity in hippocampus.
