Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

Abstract

Early onset torsion dystonia is an autosomal dominant movement disorder of variable caused by a glutamic acid, i.e. ΔE, deletion in DYT1, encoding the protein torsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (ΔE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-ΔE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies.

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

“…Bao and colleagues (2010) found that transgenic DYT1 mice were more sensitive to phasic stimulation of dopamine release, an effect which was blocked by antagonism of nicotinic receptors with mecamylamine. Furthermore, mice expressing mutation of the β2 nicotinic receptor subunit do show increased sensitivity to nicotine-induced dystonic arousal complex (O'Neill et al, 2013).…”

“…Indeed loss of the dopaminergic input in Parkinson's disease models causes profound alterations in corticostriatal synaptic plasticity (Calabresi et al, 2007b), which are associated with pruning of dendritic spines on MSNs (Ingham et al, 1989; Stephens et al, 2005; Zaja-Milatovic et al, 2005; Smith and Villalba, 2008; Villalba et al, 2009; Villalba and Smith, 2010). Likewise, reduced dopamine release and changes in corticostriatal synaptic plasticity have been indicated in multiple genetic mouse models of DYT1 dystonia (Pisani et al, 2006; Balcioglu et al, 2007; Hewett et al, 2010; Page et al, 2010; Sciamanna et al, 2012; Song et al, 2012). While decreased D1 receptor activation has been linked to changes in GNAL (Corvol et al, 2007), the primary gene involved in DYT25, these mouse models have not yet been investigated for alterations in striatal synaptic plasticity.…”

“…The mouse lines overexpressing human ΔE-torsinA were generated using as promoter either neuron-specific enolase (Shashidharan et al, 2005), the human cytomegalovirus (hMT mice; (Sharma et al, 2005)) or a murine prion protein promoter (Grundmann et al, 2007). Another transgenic mouse line overexpresses human ΔE-torsinA specifically in dopaminergic neurons of the midbrain (Page et al, 2010). In addition to overexpression models, DYT1 heterozygous knock-in mouse lines have been generated which recapitulate the trinucleotide deletion in DYT1/Tor1a gene observed most often in patients with DYT1 dystonia, and the loss of one of a pair of glutamic acid residues in the protein torsinA (Dang et al, 2005; Goodchild et al, 2005).…”

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

“…However, it has not been possible to connect the molecular and cellular consequences of torsinA dysfunction to dystonic movements, as mouse models based on the manipulation of Tor1a (or other primary dystonia-causing genes) do not exhibit overt, abnormal movements. Overexpression of DYT1 mutant torsinA in mice causes modest abnormalities in measures of beam walking, pawprint analysis, and motor learning, but not abnormal movements similar to those in patients with DYT1 dystonia (22)(23)(24). DYT1 torsinA transgenic rats reportedly show hind limb clasping during tail suspension and abnormalities in the pawprint analysis (25).…”

Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model

“…Second, they may represent a novel endophenotype, i.e., a non-motor sign in mutation carriers who do not show overt motor symptoms [22,30]. The reported endophenotypes include changes in both structure [39,44] and function of the CNS [8,15,18,19,26,34,36,39]. Further elucidating the processes involved in glutamate-mediated changes in [Ca 2+ ] c dynamics is expected to help understand the pathophysiology of E-torsinA mutation.…”