Altered nicotinamide adenine dinucleotide (NADH) fluorescence in dt^sz mutant hamsters reflects differences in striatal metabolism between severe and mild dystonia

Abstract

The dt(sz) mutant hamster represents a unique rodent model of idiopathic paroxysmal dystonia. Previous data, collected post-mortem or in anesthetized hamsters under basal conditions, indicated the critical involvement of enhanced striatal neuronal activity. To assess the importance of an enhanced striatal neuronal activity directly during a dystonic episode, continuous monitoring of changes in brain metabolism and therefore neuronal activity indirectly in awake, freely moving animals is necessary. Determination of CNS metabolism by NADH measurement by laser-induced fluorescence spectroscopy in conscious dt(sz) and nondystonic control hamsters revealed reversible decreased NADH fluorescence during dystonic episodes. The degree of change corresponded to the severity of dystonia. This study represents the first application of this innovative method in freely moving animals exhibiting a movement disorder. Our data clearly confirm that the expression of paroxysmal dystonia in dt(sz) mutant hamsters is associated with enhanced striatal neuronal activity and further underscore the versatile application of NADH fluorescence measurements in neuroscience.

Changes in dynorphin immunoreactivity but unaltered density of enkephalin immunoreactive neurons in basal ganglia nuclei of genetically dystonic hamsters

“…DYN is reflective for the neuronal activity of the direct pathway and there is evidence that DYN suppresses the responsiveness of direct pathway neurons (Steiner and Gerfen,1998). Therefore, the present finding of a significantly higher DYN ratio in the EPN of dystonic hamsters, representing higher DYN levels in relation to the area of the EPN, together with previously found higher prodynorphin mRNA expression in the ventral part of the striatum (Nobrega et al,2004) supports the suggestion that an increased activity of the direct pathway is the reason for reduced entopeduncular activity and an altered entopeduncular discharge pattern, previously detected in this animal model (Bennay et al,2001; Gernert et al,1999a, 2000, 2002; Hamann et al,2009). However, it should be noted that the DYN reactivity was not determined in the substantia nigra pars reticulata in the present study, because its neuronal activity is unaltered in the dt sz hamster (Fedrowitz et al,2002; Gernert et al,1999c).…”

“…Previous studies in the dt sz mutant revealed a significantly reduced density of different striatal GABAergic interneurons (Gernert et al,2000; Hamann et al,2005; Sander et al,2006), which represent the most important inhibitory source within the striatum (Koos et al,2004; Kreitzer,2009; Tepper et al,2008). Thus, a deficit of these interneurons causes a disinhibition of GABAergic projection neurons (Gernert et al,1999a; Hamann et al,2009).…”

Convergent evidence for abnormal striatal synaptic plasticity in dystonia

“…Other forms of dystonia exhibit the opposite trend. In the dt sz mutant hamster model of paroxysmal dystonia, an NADH fluorescence measure of striatal metabolism was reversibly increased during dystonic episodes (Hamann et al, 2009). DYT1 carriers exhibit increased glucose utilization in striatum compared to controls (Eidelberg et al, 1998).…”

Pathophysiology of dystonia

“…Previous studies indicated an involvement of a deficient activity of the striatal GABAergic interneurons with disinhibition of the striatal projection neurons [25,26] and a corticostriatal glutamatergic overactivity [27]. Previous studies indicated an involvement of a deficient activity of the striatal GABAergic interneurons with disinhibition of the striatal projection neurons [25,26] and a corticostriatal glutamatergic overactivity [27].…”