Transgenic mouse model of early-onset DYT1 dystonia

Abstract

The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, although it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the Tor1a +/D gag DYT1 dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in Tor1a +/Dgag neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in Tor1a +/Dgag mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers.

Developmental patterns of torsinA and torsinB expression

“…Imbalance in the striatal dopaminergic system is associated with generation of dystonic syndromes (Kuner et al, 2004). A transgenic mouse model of dystonia with severe behavioral abnormalities showed marked decrease in striatal dopamine levels (Shashidharan et al, 2005). Therefore, it is plausible that torsinA and torsinB play a role in the establishment of nigro-striate dopaminergic pathways.…”

“…Many mouse models of torsinA dysfunction have been generated, but each shows somewhat different phenotype (Goodchild and Dauer, 2004;Shashidharan et al, 2005;Sharma et al, 2005) emphasizing the difficulties associated with recapitulation of the disease in a mouse model. A prominent feature of the disorder is impaired motor coordination and motor learning, both of which require functional integration of multiple circuits such as frontoparietal and motor cortices, cerebellum and basal ganglia.…”

“…TorsinA mRNA and protein expression begins early in the prenatal period in the rodent and human brain (Xiao et al, 2004;Ferrari-Toninelli et al, 2004;Siegert et al, 2005). Transgenic mice overexpressing mutant human torsinA show motor abnormalities ranging from hyperkinesia to delayed motor learning, some of which begin in the early postnatal period (Goodchild and Dauer, 2004;Shashidharan et al, 2005;Sharma et al, 2005). Other reports indicate that DYT1 gene knockout mice die at birth (Dauer and Goodchild, 2004).…”

Commentary: Dopaminergic dysfunction in DYT1 dystonia

“…A variety of genetically modified mouse strains have been described that either over-express human mutant torsinA (Sharma et al, 2005;Shashidharan et al, 2005;Grundmann et al, 2007), are heterozygous for mouse mutant torsinA (Dang et al, 2005), or in which expression of endogenous torsinA is reduced (Goodchild et al, 2005;Dang et al, 2006). The recent paper by Zhao et al in Experimental Neurology (Zhao et al, 2008) characterizes anatomical, behavioral and biochemical features of one of the strains that over-express mutant human torsinA, hMT1 mice, which were generated by Sharma et al (Sharma et al, 2005).…”

Alternative Approaches to Modeling Hereditary Dystonias

“…Conversely, rodents may be more capable of compensating, and therefore loss of the protein may manifest as a lesser dysfunction compared to humans. Because the present genetic dystonia rodent models that have been generated are knock-ins, knockouts, or transgenics; the disrupted gene is present from conception [48,[57][58][59]. Embryonic alterations in gene expression may be able to compensate for the loss of gene in mice, but not in humans.…”