title: Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.
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 (torsinA(ΔE)). 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 torsinA(ΔE) 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.
authors: Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Fumiaki
authors: F
authors: Yokoi
authors: Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Huan-Xin
authors: HX
authors: Chen
authors: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors: Mai Tu
authors: MT
authors: Dang
authors: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Chad C
authors: CC
authors: Cheetham
authors: Department of Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Susan L
authors: SL
authors: Campbell
authors: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Steven N
authors: SN
authors: Roper
authors: Department of Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: J David
authors: JD
authors: Sweatt
authors: Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Yuqing
authors: Y
authors: Li
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology; D055724:Electrophysiological Phenomena / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D006579:Heterozygote; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000502:physiology
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones