Oscar H J Eelkman Rooda1, Lieke Kros2, Sade J Faneyte2, Peter J Holland3, Simona V Gornati2, Huub J Poelman2, Nico A Jansen4, Else A Tolner4, Arn M J M van den Maagdenberg4, Chris I De Zeeuw5, Freek E Hoebeek6. 1. Department of Neuroscience, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands; Department of Neurosurgery, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands. 2. Department of Neuroscience, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands. 3. School of Psychology, University of Birmingham, Birmingham, United Kingdom. 4. Department of Neurology, Leiden University Medical Center, 2300, RC Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, 2300, RC Leiden, the Netherlands. 5. Department of Neuroscience, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands; Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Sciences, 1105, BA Amsterdam, the Netherlands. 6. Department of Neuroscience, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht Medical Center, 3508, AB Utrecht, the Netherlands. Electronic address: f.e.hoebeek@umcutrecht.nl.
Abstract
BACKGROUND: Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. HYPOTHESIS: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. METHODS: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. RESULTS: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. CONCLUSION: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.
BACKGROUND:Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. HYPOTHESIS: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. METHODS: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. RESULTS: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. CONCLUSION: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.
Authors: Jan Claudius Schwitalla; Johanna Pakusch; Brix Mücher; Alexander Brückner; Dominic Alexej Depke; Thomas Fenzl; Chris I De Zeeuw; Lieke Kros; Freek E Hoebeek; Melanie D Mark Journal: Cell Mol Life Sci Date: 2022-03-19 Impact factor: 9.207