Epileptic seizures are widely regarded to occur as a result of the excitation-inhibition imbalance from a neuro-centric view. Although astrocyte-neuron interactions are increasingly recognized in seizure, elementary questions about the causal role of astrocytes in seizure remain unanswered. Here we show that optogenetic activation of channelrhodopsin-2-expressing astrocytes effectively attenuates neocortical seizures in rodent models. This anti-seizure effect is independent from classical calcium signaling, and instead related to astrocytic Na+-K+-ATPase-mediated buffering K+, which activity-dependently inhibits firing in highly active pyramidal neurons during seizure. Compared with inhibition of pyramidal neurons, astrocyte stimulation exhibits anti-seizure effects with several advantages, including a wider therapeutic window, large-space efficacy, and minimal side effects. Finally, optogenetic-driven astrocytic Na+-K+-ATPase shows promising therapeutic effects in a chronic focal cortical dysplasia epilepsy model. Together, we uncover a promising anti-seizure strategy with optogenetic control of astrocytic Na+-K+-ATPase activity, providing alternative ideas and a potential target for the treatment of intractable epilepsy.
It is essential for normal structure and function of all cell membranes. Itsprimaryfunctionsincludemaintenanceiongradientacrossmembranes 2-4 anduptakeandreleaseofneurotransmitters. 5-7 Therefore, Na+-K+-ATPaseplaysacrucialroleinionhomeostasisandcellular excitability. Dysfunction of Na+-K+-ATPasemayleadtomanytypes ofcentralnervoussystem(CNS)disorders,includingepilepsy. 8-11 Epilepsyisacommonneurologicaldisordercharacterizedbyrecurrentspontaneousseizures, 12 causedbythehighlysynchronized firingofneuronswithhyperexcitability. 13 It affects about 70 million population around the world. 14 Unfortunately, about one-third of epilepticpatientsremaindrug-resistant, 15 leadingtoasituationthat needsamoreeffectivedrugtarget.Anincreasingnumberofstudies unveiled a significant role of Na+-K+-ATPase in epilepsy. Notably, mutation of genes encoding Na+-K+-ATPase leads to epilepsy as partofitsphenotype.Inrodentmodelsofepilepsy,theactivityof Na+-K+-ATPasewasreportedtochangeaswell.Pharmacologicalinhibition of Na+-K+-ATPasewillcauseepilepticseizureinrodentsas well. Na+-K+-ATPaseactivatingantibody,bycontrast,wasreported tohaveaprotectiveeffectonepilepsy.However,discordantresults arenotuncommon,probablyduetodifferencesinetiologies,testing timing, features of various epilepsy models, etc. Hence, in this review,webrieflysummarizestructureandphysiologicalfunctionof Na+-K+-ATPaseintheCNS.Thenweaimtosummarizeandevaluate currentunderstandingsofNa+-K+-ATPaseandepilepsy,hopingto provideacomprehensiveandnovelviewontheroleofATPaseinthe epileptic brain and also therapeutic strategies associated with the
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.
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