The Role And Mechanism Of Dentate Gyrus Somatostatin-Mediated Microcircuit In Cortical Dysplasia-Related Epilepsy

Focal cortical dysplasia(FCD)represents one of the most common causes of drug-resistant epilepsy.There are mainly three subtypes of FCD based on the pathological findings,each with heterogenous manifestations and even distinct prognosis.However,factors influencing the prognosis of each subtype remain unknown.Investigation of the underlying mechism and therapeutic targets of FCD-related epilepsy is of extreme concern.We first studied presurgical information and post-surgical prognosis in 91 patients who underwent surgical treatment and had a pathological diagnosis of FCD in our center.The regression analysis indicate that patients with FCD type I and type III were more likely to experience relapses 1-year after surgery and more likely to have temporal lobe epilepsy.Electroencephalography(EEG)-magnetic resonance imaging(MRI)discordance was the independent risk factor for seizure relapses in patients with FCD type I.By contrast,patients with FCD type II had the best surgical prognosis among all subtypes and were more likely to have an extra-temporal seizure onset.MRI negativity was the independent risk factor for such patients.With intracranial EEG analysis,we further investigated the relationship between temporal lobe-related structures and seizure relapses in FCD patients.We found hippocampus with a much higher epileptogenicity index exclusively in FCD type I patients.These results indicated that the poor prognosis of FCD type I patients may be highly associatted with the high epileptogencity of hippocampus.Next,we established the prenatal freeze lesioning model,which recapitulate the pathogenesis,pathological and clinical findings in patients with FCD type I.Dentate gyrus(DG)of hippocampus were found to be highly epileptogenic in freeze-lesioned rats.Granule cells in DG also have an excitatory/inhibitory imbalance.Furthermore,somatostatin(SST)-positive neurons had a much lower density in DG of freeze-lesioned rats,wheareas the density parvalbumin(PV)-positive neurons remained almost unchanged.Further,with recording of calcium signals of SST or PV neurons,we found that DG SST neurons was much more active than controls in a generalized seizure episode.By contrast,DG PV neurons exhibited a much lower activity throughout the generalized seizure episode,when compared with controls.Selective inhibition of DG SST neurons retarded and ameliorated generalized seizures in freeze-lesioned rats,while selective activation failed to further exacerbate seizures.Selective activation of PV-positive neurons shortened generalized seizure duration but failed to retarded the progression of seizures.To further probe the “SST neuron-granule cell” microcircuit,we patch-clamped granule cells while stimulating SST neurons in vitro.Surprisingly,we found both depolarizing and hyperpolarizing currents in granule cells,and the depolarizing currents were mediated by both glutamate and gamma-aminobutyric acid.In conclusion,from clinical findings to both in vivo and in vitro investigation in animal studies,we found excitatory SST-positive neurons in DG the hub cell in FCD-related seizures.In conclusion,based on evidence from FCD patients and animal model of cortical dysplasia,we found hippocampus to be the hub region in cortical dysplasia-related epilepsy,in which the “SST neuron-granule” microcircuit in DG may take a crucial role.Our results provided the microcircuit basis underlying the epileptogenic macrocircuit in FCD type I and other late-stage malformations of cortical development.