Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery,likely due to the widespread seizure network.Previous studies have primarily focused on the disruption of dys...Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery,likely due to the widespread seizure network.Previous studies have primarily focused on the disruption of dysplastic lesions,rather than remote regions such as the hippocampus.Here,we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia.We further investigated the cellular substrates leading to the epileptic hippocampus,using multiscale tools including calcium imaging,optogenetics,immunohistochemistry and electrophysiology.For the first time,we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures.Somatostatin-positive were recruited during cortical dysplasia-related seizures.Interestingly,optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization.By contrast,parvalbumin-positive interneurons retained an inhibitory role as in controls.Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus.Taken together,our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.展开更多
Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons.Currently,antiepileptic drugs remain the main choice to control seizure,but 30%of patients are resistant to the drugs,wh...Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons.Currently,antiepileptic drugs remain the main choice to control seizure,but 30%of patients are resistant to the drugs,which calls for more research on new promising targets.Neuroinflammation is closely associated with the development of epilepsy.As an important inflammatory factor,high mobility group protein B1(HMGB1)has shown elevated expression and an increased proportion of translocation from the nucleus to the cytoplasm in patients with epilepsy and in multiple animal models of epilepsy.HMGB1 can act on downstream receptors such as Toll-like receptor 4 and receptor for advanced glycation end products,thereby activating interleukin(IL)-1βand nuclear factor kappa-B(NF-κB),which in turn act with glutamate receptors such as the N-methyl-D-aspartate(NMDA)receptors to aggravate hyperexcitability and epilepsy.The hyperexcitability can in turn stimulate the expression and translocation of HMGB1.Blocking HMGB1 and its downstream signaling pathways may be a direction for antiepileptic drug therapy.Here,we review the changes of HMGB1-related pathway in epileptic brains and its role in the modulation of neuronal excitability and epileptic seizure.Furthermore,we discuss the potentials of HMGB1 as a therapeutic target for epilepsy and provide perspective on future research on the role of HMGB1 signaling in epilepsy.展开更多
基金supported by grants from the National Key R&D Program of China(No.2020YFA0803900)the National Natural Science Foundation of China(82071443,81973298,82173796,82022071,82201607)the Natural Science Foundation of Zhejiang Province(LD22H310003,Q23H090002).
文摘Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery,likely due to the widespread seizure network.Previous studies have primarily focused on the disruption of dysplastic lesions,rather than remote regions such as the hippocampus.Here,we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia.We further investigated the cellular substrates leading to the epileptic hippocampus,using multiscale tools including calcium imaging,optogenetics,immunohistochemistry and electrophysiology.For the first time,we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures.Somatostatin-positive were recruited during cortical dysplasia-related seizures.Interestingly,optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization.By contrast,parvalbumin-positive interneurons retained an inhibitory role as in controls.Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus.Taken together,our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.
基金supported by grants from the National Natural Science Foundation of China(81630098,and 81973298).
文摘Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons.Currently,antiepileptic drugs remain the main choice to control seizure,but 30%of patients are resistant to the drugs,which calls for more research on new promising targets.Neuroinflammation is closely associated with the development of epilepsy.As an important inflammatory factor,high mobility group protein B1(HMGB1)has shown elevated expression and an increased proportion of translocation from the nucleus to the cytoplasm in patients with epilepsy and in multiple animal models of epilepsy.HMGB1 can act on downstream receptors such as Toll-like receptor 4 and receptor for advanced glycation end products,thereby activating interleukin(IL)-1βand nuclear factor kappa-B(NF-κB),which in turn act with glutamate receptors such as the N-methyl-D-aspartate(NMDA)receptors to aggravate hyperexcitability and epilepsy.The hyperexcitability can in turn stimulate the expression and translocation of HMGB1.Blocking HMGB1 and its downstream signaling pathways may be a direction for antiepileptic drug therapy.Here,we review the changes of HMGB1-related pathway in epileptic brains and its role in the modulation of neuronal excitability and epileptic seizure.Furthermore,we discuss the potentials of HMGB1 as a therapeutic target for epilepsy and provide perspective on future research on the role of HMGB1 signaling in epilepsy.
