Motor Deficits and Hyperactivity in Cerebral Cortex-specific Dyt1 Conditional Knockout Mice

Abstract

DYT1 dystonia is a primary generalized early-onset torsion dystonia caused by mutations in DYT1 that codes for torsinA and has an autosomal dominant inheritance pattern with approximately 30% penetrance. Abnormal activity in the pallidal-thalamic-cortical circuit, especially in the globus pallidus internus, is the proposed cause of dystonic symptoms. However, recent neuroimaging studies suggest significant contribution of the cerebral cortex. To understand the contribution of the cerebral cortex to dystonia, we produced cerebral cortex-specific Dyt1 conditional knockout mice and analysed their behaviour. The conditional knockout mice exhibited motor deficits and hyperactivity that mimic the reported behavioural deficits in Dyt1 DeltaGAG knockin heterozygous and Dyt1 knockdown mice. Although the latter two mice exhibit lower levels of dopamine metabolites in the striatum, the conditional knockout mice did not show significant alterations in the striatal dopamine and its metabolites levels. The conditional knockout mice had well-developed whisker-related patterns in somatosensory cortex, suggesting formations of synapses and neural circuits were largely unaffected. The results suggest that the loss of torsinA function in the cerebral cortex alone is sufficient to induce behavioural deficits associated with Dyt1 DeltaGAG knockin mutation. Developing drugs targeting the cerebral cortex may produce novel medical treatments for DYT1 dystonia patients.

Abnormal striatal and thalamic dopamine neurotransmission

“…10,11 A conditional knockout mouse with selective torsinA deficits in the cerebral cortex had motor abnormalities reminiscent of dystonia, but no changes in striatal DA metabolism. 12 Similar inconsistencies have also been found in non-DYT1 experimental models of dystonia. [13][14][15][16] In the current study, we sought to identify changes in D 2 receptor availability linked to the presence of clinical manifestations in a cohort of DYT1 and DYT6 gene carriers.…”

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

“…Dyt1 homozygous KO mice, Dyt1 ÁGAG heterozygous KI mice, paternally inherited Sgce heterozygous KO mice and Sgce homozygous KO mice were prepared and genotyped by PCR as described earlier (12,17,27,36 …”

TorsinA and the Pathophysiology of DYT1 Dystonia

“…These findings suggest that torsinA is an essential protein for postnatal survival, and that ΔGAG is a loss of function mutation. In a more recent study, similar motor deficits were reported in a cortex-specific DYT1 knock-out model (Yokoi et al, 2008). The authors suggest that loss of torsinA in the cerebral cortex alone is sufficient to mimic behavioral deficits noticed in heterozygous ΔGAG knock-in and DYT1 knock-down mice.…”

“…Several murine models of DYT1 dystonia have been developed, and characterized to various degrees (Dang et al, 2005;Sharma et al, 2005;Shashidharan et al, 2005;Dang et al, 2006;Grundmann et al, 2007;Yokoi et al, 2008). These models include DYT1 knock-out , cortex-specific DYT1 knock-out (Yokoi et al, 2008), torsinA knock-down (Dang et al, 2006), transgenic overexpression of mutant and wild-type torsinA (Sharma et al, 2005;Shashidharan et al, 2005;Grundmann et al, 2007), and DYT1 ΔGAG knock-in (Dang et al, 2005; mouse models.…”

“…These models include DYT1 knock-out , cortex-specific DYT1 knock-out (Yokoi et al, 2008), torsinA knock-down (Dang et al, 2006), transgenic overexpression of mutant and wild-type torsinA (Sharma et al, 2005;Shashidharan et al, 2005;Grundmann et al, 2007), and DYT1 ΔGAG knock-in (Dang et al, 2005; mouse models. In the DYT1 ΔGAG knock-in mouse model, a GAA trinucleotide deletion was made to mimic the GAG deletion in human DYT1 mutation, which was supposed to encode one of the glutamic acids at the position corresponding to human E302/303.…”