RESUMEN
Cortical dysplasia is the most common etiology of intractable epilepsy. Both excitability changes in cortical neurons and neural network reconstitution play a role in cortical dysplasia epileptogenesis. Recent research shows that the axon initial segment, a subcompartment of the neuron important to the shaping of action potentials, adjusts its position in response to changes in input, which contributes to neuronal excitability and local circuit balance. It is unknown whether axon initial segment plasticity occurs in neurons involved in seizure susceptibility in cortical dysplasia. Here, we developed a "Carmustine"- "pilocarpine" rat model of cortical dysplasia and show that it exhibits a lower seizure threshold, as indicated by behavior studies and electroencephalogram monitoring. Using immunofluorescence, we measured the axon initial segment positions of deep L5 somatosensory neurons and show that it is positioned closer to the soma after acute seizure, and that this displacement is sustained in the chronic phase. We then show that Nifedipine has a dose-dependent protective effect against axon initial segment displacement and increased seizure susceptibility. These findings further our understanding of the pathophysiology of seizures in cortical dysplasia and suggests Nifedipine as a potential therapeutic agent.
Asunto(s)
Segmento Inicial del Axón/fisiología , Modelos Animales de Enfermedad , Malformaciones del Desarrollo Cortical/fisiopatología , Plasticidad Neuronal/fisiología , Convulsiones/fisiopatología , Animales , Axones/efectos de los fármacos , Axones/fisiología , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/dietoterapia , Susceptibilidad a Enfermedades/fisiopatología , Electroencefalografía/efectos de los fármacos , Electroencefalografía/métodos , Femenino , Malformaciones del Desarrollo Cortical/inducido químicamente , Malformaciones del Desarrollo Cortical/tratamiento farmacológico , Nifedipino/farmacología , Nifedipino/uso terapéutico , Pilocarpina/toxicidad , Embarazo , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
BACKGROUND: The axon initial segment (AIS) is a specialized membrane region in the axon of neurons wherein numerous specific voltage-gated sodium channels (VGSCs) are clustered and action potentials are initiated. The AIS is currently considered as a new plastic hotspot. METHODS: We investigated the alterations in Nav1.6 (SCN8A) and its adapter protein ankyrin G in the AIS of the hippocampal cornu ammonis 3 (CA3) pyramidal cells of rat after status epilepticus induced by lithium-pilocarpine (PISE). RESULTS: Nav1.6 and ankyrin G were colocalized in the AIS of hippocampal CA3 pyramidal neurons. Compared with the control group, the protein and mRNA expression of Nav1.6 increased within 24 h and 60 days after PISE. By contrast, ankyrin G protein expression decreased slightly within 24 h but increased within 60 days, whereas ankyrin G mRNA increased within 24 h and 60 days after PISE. However, the protein and mRNA expression levels of Nav1.6 and ankyrin G within 7 days after PISE did not differ significantly with those of the control. CONCLUSIONS: Nav1.6 and ankyrin G may participate in the plastic changes in the AIS of hippocampus CA3 neurons after PISE and play potential roles in epileptogenesis by regulating neuronal excitability.