Abstract

The work described in this thesis was performed in order to elucidate the role of different cerebellar modules in ataxia and generalized epilepsy using various techniques including in vivo electrophysiology, optogenetics, pharmacological interventions, immunohistology and behavioral measurements. The majority of experiments were executed in mice with mutations in the Cacna1a gene which encodes the poreforming subunit of Cav2.1 calcium channels. Expression of this gene is particularly high in the cerebellum and mutations or ablation of this gene can result in cerebellar ataxia, dystonia and generalized epilepsy. In Chapter 2 we showed that PC specific deletion of this gene is sufficient to cause cerebellar ataxia and widespread PC degeneration. Interestingly, the ataxic phenotype became apparent well before any morphological or degenerative changes occurred. This suggests that, in line with other studies, aberrant PC activity rather than PC atrophy or morphological anomalies may play a crucial role in cerebellar ataxia. Next we investigated potential cerebellar involvement in generalized epilepsy using a global Cacna1a mutant (tottering) and tested whether manipulation of either cerebellar nuclei or cerebellar cortex activity could influence seizure occurrence. In Chapters 3 and 5 we demonstrate that both CN neurons and PCs show GSWD related firing pattern modulation. Furthermore, whereas pharmacological manipulation of CN activity had a pronounced impact on seizure occurrence, stopping action potential firing in a large area of the cerebellar cortex had no impact on GSWD occurrence. Considering the promising effects of these pharmacological interventions in the CN, we next described the use of a closed-loop seizure detection and stimulation system with the aim of disrupting epileptic thalamocortical activity through optogenetic CN stimulation in Chapters 3 and 4. We showed that this form of on-demand neurostimulation is highly effective and stopped 75-100% of the seizures within a few hundred milliseconds. To exclude specificity of these results for this particular mouse model we confirmed our main outcomes in an unrelated absence epilepsy mouse model. In Chapter 6 we discuss potential mechanisms underlying the effects of pharmacological and optogenetic CN modulation and found that thalamic neurons indeed showed a change in activity upon CN manipulations. Chapter 7 provided conclusive remarks and a discussion of the implications of these results and suggestions for future research.

Additional Metadata
Keywords Cerebellum, Ataxia, Epilepsy
Promotor C.I. de Zeeuw (Chris)
Publisher Erasmus University Rotterdam
ISBN 978-94-6299-039-5
Persistent URL hdl.handle.net/1765/78049
Note Due to embargo regulations and unpublished data RePub contains an edited version of this thesis.
Citation
Kros, L. (2015, April 29). Cerebellar Involvement in Ataxia and Generalized Epilepsy. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/78049


Additional Files
4202_Kros-Lieke.jpg Cover Image , 21kb
02_purkinje_cell-specific_ablation.pdf Final Version , 17mb
03_cerebellar_output_controls.pdf Final Version , 4mb
04_an_implementation_of_a_wavelet-based.pdf Final Version , 2mb
08_appendix.pdf Final Version , 334kb
Stellingen-L-Kros.pdf , 12kb

See Also