Short-term stimulations of the entopeduncular nucleus induce cerebellar changes of c-Fos expression in an animal model of paroxysmal dystonia

Abstract

Deep brain stimulation (DBS) of the globus pallidus internus (entopeduncular nucleus, EPN, in rodents) is important for the treatment of drug-refractory dystonia. The pathophysiology of this movement disorder and the mechanisms of DBS are largely unknown. Insights into the mechanisms of DBS in animal models of dystonia can be helpful for optimization of DBS and add-on therapeutics. We recently found that short-term EPN-DBS with 130 Hz (50 µA, 60 µs) for 3 h improved dystonia in dt^sz hamsters and reduced spontaneous excitatory cortico-striatal activity in brain slices of this model, indicating fast effects on synaptic plasticity. Therefore, in the present study, we examined if these effects are related to changes of c-Fos, a marker of neuronal activity, in brains derived from dt^sz hamsters after these short-term DBS or sham stimulations. After DBS vs. sham, c-Fos intensity was increased around the electrode, but the number of c-Fos⁺ cells was not altered within the whole EPN and projection areas (habenula, thalamus). DBS did not induce changes in striatal and cortical c-Fos⁺ cells as GABAergic (GAD67⁺ and parvalbumin-reactive) neurons in motor cortex and striatum. Unexpectedly, c-Fos⁺ cells were decreased in deep cerebellar nuclei (DCN) after DBS, suggesting that cerebellar changes may be involved in antidystonic effects already during short-term DBS. However, the present results do not exclude functional changes within the basal ganglia-thalamo-cortical network, which will be further investigated by long-term EPN stimulations. The present study indicates that the cerebellum deserves attention in ongoing examinations on the mechanisms of DBS in dystonia.

Keywords: Animal models; Basal ganglia; Cerebellum; Deep brain stimulation; Dystonia; Neuronal activity.