Abstract
DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.
Highlights
Dystonia is clinically defined as sustained muscle contractions that often involve both agonist and antagonist muscles, causing twisting and repetitive movements or abnormal postures [1, 2]
The results suggest that the decreased torsinA function resulting from a single null allele is sufficient to exhibit motor deficits
Since mice can hold onto the rotarod with four paws and the latency to fall is an indicator of total motor performance, the results suggest no significant motor symptoms in total motor performance with four paws
Summary
Dystonia is clinically defined as sustained muscle contractions that often involve both agonist and antagonist muscles, causing twisting and repetitive movements or abnormal postures [1, 2]. The most common generalized, early-onset form of dystonia is DYT1 dystonia [Oppenheim’s dystonia; Online Mendelian Inheritance in Man (OMIM) identifier #128100, Dystonia 1]. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid (torsinAΔE) at 302 or 303 amino acid position in the carboxyl terminal region [5]. Homozygous DYT1 ΔGAG mutation carriers have not been reported in humans. The ΔGAG mutation is the most common mutation, an 18 bp in-frame deletion mutation corresponding to 323–328 amino acid position [8,9,10], a 4 bp-deletion mutation resulting in a frame-shift at 311 amino acid position and a premature stop codon at 325 position [11], and an Arg288Gln missense mutation [12] have been reported. Whether torsinAΔE leads to loss-of-function, toxicgain-of-function, or both remains unknown
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