Pre-Synaptic Release Deficits in a DYT1 Dystonia Mouse Model

dc.contributor.authorYokoi, Fumiakien
dc.contributor.authorCheetham, Chad C.en
dc.contributor.authorCampbell, Susan L.en
dc.contributor.authorSweatt, J. Daviden
dc.contributor.authorLi, Yuqingen
dc.contributor.departmentAnimal and Poultry Sciencesen
dc.description.abstractDYT1 early-onset generalized torsion dystonia (DYT1 dystonia) is an inherited movement disorder caused by mutations in one allele of DYT1 (TOR1A), coding for torsinA. The most common mutation is a trinucleotide deletion (DGAG), which causes a deletion of a glutamic acid residue (DE) in the C-terminal region of torsinA. Although recent studies using cultured cells suggest that torsinA contributes to protein processing in the secretory pathway, endocytosis, and the stability of synaptic proteins, the nature of how this mutation affects synaptic transmission remains unclear. We previously reported that thetaburst- induced long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not altered in Dyt1 DGAG heterozygous knock-in (KI) mice. Here, we examined short-term synaptic plasticity and synaptic transmission in the hippocampal slices. Field recordings in the hippocampal Schaffer collaterals (SC) pathway revealed significantly enhanced paired pulse ratios (PPRs) in Dyt1 DGAG heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell recordings from the CA1 neurons showed that Dyt1 DGAG heterozygous KI mice exhibited normal miniature excitatory post-synaptic currents (mEPSC), suggesting that action-potential independent spontaneous pre-synaptic release was normal. On the other hand, there was a significant decrease in the frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents (sEPSC) in Dyt1 DGAG heterozygous KI mice, suggesting that the action-potential dependent pre-synaptic release was impaired. Moreover, hippocampal torsinA was significantly reduced in Dyt1 DGAG heterozygous KI mice. Although the hippocampal slice model may not represent the neurons directly associated with dystonic symptoms, impaired release of neurotransmitters caused by partial dysfunction of torsinA in other brain regions may contribute to the pathophysiology of DYT1 dystonia.en
dc.description.sponsorshipThis work was supported by Tyler’s Hope for a Dystonia Cure, Inc., National Institutes of Health grants (NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72872, and NS 74423), Howard Hughes Med-Grad Graduate Fellowship (CCC), and startup funds from the Lucille P. Markey Charitable Trust (UIUC) and Department of Neurology (UAB). Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.format.extent7 pagesen
dc.identifier.citationYokoi F, Cheetham CC, Campbell SL, Sweatt JD, Li Y (2013) Pre-Synaptic Release Deficits in a DYT1 Dystonia Mouse Model. PLoS ONE 8(8): e72491. doi:10.1371/journal.pone.0072491en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.titlePre-Synaptic Release Deficits in a DYT1 Dystonia Mouse Modelen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden


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