Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 52, Pages 27084-27094Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908176117
Keywords
seizure; deep brain stimulation; basal ganglia; optogenetics; substantia nigra
Categories
Funding
- GeorgetownHoward University Clinical and Translational Science Award [UL1TR000101]
- Georgetown University Dean for Research
- American Epilepsy Society/Epilepsy Foundation of America [367405]
- [R01NS097762]
- [F30NS110318]
- [R21AA027171]
- [R01AA027660]
- [KL2TR001432]
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Three decades of studies have shown that inhibition of the substantia nigra pars reticulata (SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN. Inhibition of cell bodies in SNpr suppressed generalized seizures evoked by pentylenetetrazole (PTZ), partial seizures evoked from the fore-brain, absence seizures evoked by gamma-butyrolactone (GBL), and audiogenic seizures in genetically epilepsy-prone rats. Strikingly, these effects were fully recapitulated by silencing nigrotectal projections. By contrast, silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ. These data underscore the broad-spectrum anticonvulsant efficacy of this circuit, and demonstrate that specific efferent projection pathways differentially control different seizure types.
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