PMID- 23967309
OWN - NLM
STAT- MEDLINE
DCOM- 20140514
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - Pre-synaptic release deficits in a DYT1 dystonia mouse model.
PG  - e72491
LID - 10.1371/journal.pone.0072491 [doi]
LID - e72491
AB  - DYT1 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 (DeltaGAG), which 
      causes a deletion of a glutamic acid residue (DeltaE) 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 theta-burst-induced 
      long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not 
      altered in Dyt1 DeltaGAG 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 DeltaGAG 
      heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell 
      recordings from the CA1 neurons showed that Dyt1 DeltaGAG 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 DeltaGAG heterozygous KI mice, suggesting that the action-potential dependent 
      pre-synaptic release was impaired. Moreover, hippocampal torsinA was 
      significantly reduced in Dyt1 DeltaGAG 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.
FAU - Yokoi, Fumiaki
AU  - Yokoi F
AD  - Department of Neurology, College of Medicine, University of Florida, Gainesville, 
      Florida, USA.
FAU - Cheetham, Chad C
AU  - Cheetham CC
FAU - Campbell, Susan L
AU  - Campbell SL
FAU - Sweatt, J David
AU  - Sweatt JD
FAU - Li, Yuqing
AU  - Li Y
LA  - eng
GR  - NS37409/NS/NINDS NIH HHS/United States
GR  - P30 NS057098/NS/NINDS NIH HHS/United States
GR  - NS47692/NS/NINDS NIH HHS/United States
GR  - NS65273/NS/NINDS NIH HHS/United States
GR  - R21 NS047692/NS/NINDS NIH HHS/United States
GR  - NS47466/NS/NINDS NIH HHS/United States
GR  - R01 MH057014/MH/NIMH NIH HHS/United States
GR  - P01 NS037409/NS/NINDS NIH HHS/United States
GR  - R21 NS072872/NS/NINDS NIH HHS/United States
GR  - P30 NS047466/NS/NINDS NIH HHS/United States
GR  - NS 74423/NS/NINDS NIH HHS/United States
GR  - NS54246/NS/NINDS NIH HHS/United States
GR  - R03 NS074423/NS/NINDS NIH HHS/United States
GR  - NS57098/NS/NINDS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R21 NS065273/NS/NINDS NIH HHS/United States
GR  - R01 NS054246/NS/NINDS NIH HHS/United States
GR  - NS72872/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130813
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Dyt1 protein, mouse)
RN  - 0 (Molecular Chaperones)
SB  - IM
MH  - Animals
MH  - CA1 Region, Hippocampal/metabolism
MH  - Disease Models, Animal
MH  - Dystonia Musculorum Deformans/*genetics/*metabolism
MH  - Heterozygote
MH  - Long-Term Potentiation
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Chaperones/*genetics/metabolism
MH  - Neurons/metabolism
MH  - Presynaptic Terminals/*metabolism
MH  - Synaptic Potentials
PMC - PMC3742515
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/24 06:00
MHDA- 2014/05/16 06:00
PMCR- 2013/08/13
CRDT- 2013/08/23 06:00
PHST- 2011/11/14 00:00 [received]
PHST- 2013/07/17 00:00 [accepted]
PHST- 2013/08/23 06:00 [entrez]
PHST- 2013/08/24 06:00 [pubmed]
PHST- 2014/05/16 06:00 [medline]
PHST- 2013/08/13 00:00 [pmc-release]
AID - PONE-D-11-22542 [pii]
AID - 10.1371/journal.pone.0072491 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 13;8(8):e72491. doi: 10.1371/journal.pone.0072491. eCollection 
      2013.