Synchronicity and rhythmicity of purkinje cell firing during generalized spike-and-wave discharges in a natural mouse model of absence epilepsy

Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, headrestrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure-related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations

Optimization of input parameters to a CN neuron model to simulate its activity during and between epileptic absence seizures

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Combining machine learning and simulations of a morphologically realistic model to study modulation of neuronal activity in cerebellar nuclei

Abstract from 23rd Annual Computational Neuroscience Meeting: CNS 2014 © 2014 Alva et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Epileptic absence seizures are characterized by synchronized oscillatory activity in the cerebral cortex that can be recorded as so-called spike-and-wave discharges (SWDs) by electroencephalogram. Although the cerebral cortex and the directly connected thalamus are paramount to this particular form of epilepsy, several other parts of the mammalian brain are likely to influence this oscillatory activity. We have recently shown that some of the cerebellar nuclei (CN) neurons, which form the main output of the cerebellum, show synchronized oscillatory activity during episodes of cortical SWDs in two independent mouse models of absence epilepsy [1]. The CN neurons that show this significant correlation with the SWDs are deemed to “participate” in the seizure activity and are therefore used in our current study designed to unravel the potential causes of such oscillatory firing patternsPeer reviewe

Controlling Cerebellar Output to Treat Refractory Epilepsy

Generalized epilepsy is characterized by recurrent seizures caused by oscillatory neuronal firing throughout thalamocortical networks. Current therapeutic approaches often intervene at the level of the thalamus or cerebral cortex to ameliorate seizures. We review here the therapeutic potential of cerebellar stimulation. The cerebellum forms a prominent ascending input to the thalamus and, whereas stimulation of the foliated cerebellar cortex exerts inconsistent results, stimulation of the centrally located cerebellar nuclei (CN) reliably stops generalized seizures in experimental models. Stimulation of this area indicates that the period of stimulation with respect to the phase of the oscillations in thalamocortical networks can optimize its effect, opening up the possibility of developing on-demand deep brain stimulation (DBS) treatments

Differentiating Cerebellar Impact on Thalamic Nuclei

The cerebellum plays a role in coordination of movements and non-motor functions. Cerebellar nuclei (CN) axons connect to various parts of the thalamo-cortical network, but detailed information on the characteristics of cerebello-thalamic connections is lacking. Here, we assessed the cerebellar input to the ventrolateral (VL), ventromedial (VM), and centrolateral (CL) thalamus. Confocal and electron microscopy showed an increased density and size of CN axon terminals in VL compared to VM or CL. Electrophysiological recordings in vitro revealed that optogenetic CN stimulation resulted in enhanced charge transfer and action potential firing in VL neurons compared to VM or CL neurons, despite that the paired-pulse ratio was not significantly different. Together, these findings indicate that the impact of CN input onto neurons of different thalamic nuclei varies substantially, which highlights the possibility that cerebellar output differentially controls various parts of the thalamo-cortical network

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

BACKGROUND: Epileptic (absence) seizures in 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 synchronized thalamo-cortical rhythmic 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 electrocorticogram 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

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome. [Erratum]

In the originally published version of this article, author name Ana Chkhaidze was misspelled in the author list. This has now been corrected