Spontaneous Remission of Paroxysmal Dystonia Coincides with Normalization of Entopeduncular Activity indt^szMutants

Abstract

Recent studies have shown a dramatically decreased spontaneous discharge rate of entopeduncular neurons in a unique animal model of idiopathic paroxysmal dystonia, the dt(sz) mutant hamster. These changes were found in animals at the age at which the most marked expression of dystonia is usually observed. In this rodent model, the age-dependent disappearance of stress-inducible dystonic attacks at an age of approximately 10 weeks allows investigations of the relevance of pathophysiological changes for the occurrence of dystonia by ontogenetic studies. Therefore, we examined the entopeduncular activity by extracellular single unit recordings in groups of dt(sz) mutants and nondystonic control hamsters at 17-22 weeks of age. In contrast to recent findings, after the complete remission of dystonia, the mean discharge rate of entopeduncular neurons in dt(sz) mutants (28.1 +/- 1.2 spikes/sec) was similar to that of age-matched nondystonic control hamsters (30.8 +/- 0.9 spikes/sec). Thus, the disappearance of paroxysmal dystonia is accompanied by a normalization of the entopeduncular activity in dt(sz) mutants. The present data clearly demonstrate the fundamental importance of a decreased basal ganglia output for the expression of paroxysmal dystonia.

Spontaneous Pallidal Neuronal Activity in Human Dystonia: Comparison With Parkinson’s Disease and Normal Macaque

“…Reduced pallidal outflow in dystonia is also consistent with studies in a rodent model of genetic dystonia, the dt-sz hamster, in which spontaneous discharge in the entopendular nucleus (rodent homologue of GPi) was reduced in the dystonic state compared with the normal state (Bennay et al 2001).…”

Effects of locally administered pentylenetetrazole on nigral single unit activity and severity of dystonia in a genetic model of paroxysmal dystonia

“…Although the antidystonic activity of PTZ after intranigral administration was moderate at the examined dose, it can be concluded from the present findings that the PTZinduced increase of the nigral discharge rate is not relevant for the aggravation of dystonia in mutant hamsters systemically treated with PTZ (Fredow and Löscher, 1991). Thus, the present finding and previous electrophysiological data on the SNr activity (Gernert et al, 1999c) do not argue against the hypothesis that a reduced basal ganglia output, particularly a decreased entopeduncular inhibition of thalamic nuclei, plays a critical role in paroxysmal dystonia (Gernert et al, 2000;Bennay et al, 2001). It should be noted that the present electrophysiological data, substantiating an unaltered spontaneous discharge rate of neurons in the SNr (Gernert et al, 1999c), were obtained from anesthetized mutant hamsters in the absence of dystonic attacks.…”

“…Previous experiments in mutant hamsters have shown several changes within thalamic nuclei during dystonic attacks and in the absence of dystonia (e.g., Löscher and Hörstermann, 1992;Nobrega et al, 1995). These thalamic changes probably, at least in part, are due to the lowered basal ganglia output (Gernert et al, 2000;Bennay et al, 2001). With the suggestion that disinhibition of thalamic nuclei is an essential component in paroxysmal dystonia of dt sz hamsters, a PTZ-induced increase of the activity of SNr neurons should exert beneficial effects.…”

High-frequency stimulation of the entopeduncular nucleus improves dystonia in dtsz hamsters

“…GPi) which in turn disinhibit motor thalamus and cortex [5,6,15]. This hypothesis is not only supported by electrophysiological findings in dystonian patients who show a reduced discharge rate and an altered discharge pattern of GPi neurons [7,8], but also by extracellular recordings in EPN neurons of the dt sz hamster at its most sensitive age for dystonia [9][10][11].…”

“…This hypothesis is supported by electrophysiological findings in dystonian patients in which microelectrode recordings of GPi neurons revealed a reduced discharge rate and also an altered discharge pattern [7,8]. Intriguingly, the dt sz hamster shows also these abnormalities as evidenced by extracellular recordings that revealed a reduced neuronal firing rate and an abnormal discharge pattern within the entopeduncular nucleus (EPN, the homologue of the GPi in rodents) [9][10][11].…”