title: Cerebellar output controls generalized spike-and-wave discharge occurrence.
abstract: OBJECTIVE
  Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures.
  
  
  METHODS
  Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures.
  
  
  RESULTS
  We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds.
  
  
  CONCLUSIONS
  CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated.
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Lieke
authors.initials: L
authors.lastname: Kros
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Oscar H J
authors.initials: OH
authors.lastname: Eelkman Rooda
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Spanke
authors.affiliation: Science and Technology Research Institute, University of Hertfordshire, Hatfield, United Kingdom.
authors.forename: Parimala
authors.initials: P
authors.lastname: Alva
authors.affiliation: Bioelectronics Section, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, the Netherlands.
authors.forename: Marijn N
authors.initials: MN
authors.lastname: van Dongen
authors.affiliation: Bioelectronics Section, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, the Netherlands.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Karapatis
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Else A
authors.initials: EA
authors.lastname: Tolner
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Christos
authors.initials: C
authors.lastname: Strydis
authors.affiliation: Science and Technology Research Institute, University of Hertfordshire, Hatfield, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Davey
authors.affiliation: Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Sciences, Amsterdam, the Netherlands.
authors.forename: Beerend H J
authors.initials: BH
authors.lastname: Winkelman
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: Negrello
authors.affiliation: Bioelectronics Section, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, the Netherlands.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: Serdijn
authors.affiliation: Science and Technology Research Institute, University of Hertfordshire, Hatfield, United Kingdom.
authors.forename: Volker
authors.initials: V
authors.lastname: Steuber
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Sciences, Amsterdam, the Netherlands.
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Freek E
authors.initials: FE
authors.lastname: Hoebeek
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics; D002529:Cerebellar Nuclei / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000503:physiopathology*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D062308:Optogenetics; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology
chemical_list: D020864:Calcium Channels, N-Type; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists