Altered Discharge Pattern of Basal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia

Abstract

A decreased activity of basal ganglia output neurons is thought to underlie idiopathic dystonias and other hyperkinetic movement disorders. We found recently a reduced spontaneous discharge rate of entopeduncular neurons (internal globus pallidus in primates) in dt(sz) hamsters, an unique model for idiopathic paroxysmal dystonia in which stress-inducible attacks show an age-dependent severity. Otherwise, it has been suggested that an altered discharge pattern may be more important for the occurrence of dystonia than a reduced discharge rate. Based on qualitative and computerized quantitative evaluations of interspike interval histograms and spike trains of extracellularly recorded single neurons, we investigated the spontaneous discharge pattern of GABAergic entopeduncular and nigral neurons in dt(sz) hamsters at different ages. The discharge pattern of entopeduncular neurons was highly irregular and showed an altered burst-like firing in dt(sz) hamsters at the age of the most marked expression of dystonia when compared with age-matched nondystonic controls. In line with a recently reported normalization of discharge rates after age-dependent disappearance of dystonia, we found an almost complete normalization of the discharge pattern of entopeduncular neurons after remission of dystonia in dt(sz) hamsters. Investigations of GABAergic nigral neurons, reported recently to have the same spontaneous discharge rates in dystonic and nondystonic hamsters, did not show an altered firing pattern in dt(sz) hamsters. The present data clearly indicate the fundamental importance of an altered discharge pattern of entopeduncular neurons for the expression of paroxysmal dystonia, and probably also for other dyskinesias, and may explain the improvements obtained by pallidotomy in dystonic patients despite an obviously reduced pallidal output.

Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome

“…symptoms disappear (40). Similarly irregular firing patterns have also been recorded in the GPi of humans either with severe dystonia or severe TS (41).…”

Impaired sequence learning in carriers of the DYT1 dystonia mutation

“…Recent electrophysiological studies have attributed dystonia to an altered pattern of pallidal output with burst firing and highly irregular interspike frequencies. 32,33 If present to a lesser degree in nonmanifesting dystonia gene carriers, this subcortical noise source may interfere with the functioning of corticostriatopallidothalamocortical and related pathways, and with associated aspects of motor behavior including the learning of sequences. Nonetheless, the possibility of an inherent genetically mediated abnormality in frontostriatal connectivity cannot be excluded.…”

Animal models of generalized dystonia

“…In these models, abnormal nigrostriatal dopaminergic neurotransmission 19,20,39,40,44 accompanied by neurophysiological irregularities predict disorganized thalamocortical signaling that may drive the dystonia. 22,24,119 In contrast, the models of dystonia implicating the cerebellum predict abnormal cerebellar signaling, including Purkinje cells and deep cerebellar nuclei, with involvement of the entire olivocerebellar system. 56,59,115 Moreover, selectively eliminating cerebellar output in these cases blocks the dystonia.…”

“…In the absence of dystonic attacks, recordings of single unit activity demonstrate significant reductions in spontaneous discharge rate and irregular burst morphology within the dt sz entopeduncular nucleus, suggesting physiological abnormalities observed within striatum result in increased entopeduncular inhibition. 15,24 Interestingly, entopeduncular physiological abnormalities are age dependent and are detectable only in attack-prone animals. 12,24 Thus, the aberrant neurophysiological activity detected within the dt sz basal ganglia point to dysfunctional output from the entopeduncolothalamic pathway in the generation of dystonia.…”

“…15,24 Interestingly, entopeduncular physiological abnormalities are age dependent and are detectable only in attack-prone animals. 12,24 Thus, the aberrant neurophysiological activity detected within the dt sz basal ganglia point to dysfunctional output from the entopeduncolothalamic pathway in the generation of dystonia.…”