PMID- 28087735
OWN - NLM
STAT- MEDLINE
DCOM- 20170515
LR  - 20171217
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 26
IP  - 6
DP  - 2017 Mar 15
TI  - Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in 
      dystrophin-deficient mdx mice.
PG  - 1041-1055
LID - 10.1093/hmg/ddx013 [doi]
AB  - Alterations in the Duchenne muscular dystrophy (DMD) gene have been associated 
      with enhanced stress reactivity in vertebrate species, suggesting a role for 
      brain dystrophin in fear-related behavioral and cognitive processes. Because the 
      loss of dystrophin (Dp427) reduces clustering of central gamma-aminobutyric acid 
      (GABAA) receptors, it is suspected that local inhibitory tuning and modulation of 
      neuronal excitability are perturbed in a distributed brain circuit that normally 
      controls such critical behavioral functions. In this study, we undertook a 
      large-scale behavioral study to evaluate fear-related behavioral disturbances in 
      dystrophin-deficient mdx mice. We first characterized the behavioral determinants 
      of the enhanced fearfulness displayed by mdx mice following mild acute stress and 
      its association with increased anxiety and altered fear memories. We further 
      demonstrated that this enhanced fearfulness induces long-lasting motor 
      inhibition, suggesting that neurobehavioral dysfunctions significantly influence 
      motor outcome measures in this model. We also found that mdx mice are more 
      sensitive to the sedative and hypnotic effects of 
      4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochlorid (THIP), a selective 
      pharmacological activator of extrasynaptic GABAA receptors involved in central 
      tonic inhibition. Our results highlight that information on the emotional aspects 
      of mdx mice are important to better understand the bases of intellectual and 
      neuropsychiatric defects in DMD and to better define valuable functional readouts 
      for preclinical studies. Our data also support the hypothesis that altered 
      spatial localization of GABAA receptors due to Dp427 loss is a pathological 
      mechanism associated with brain dysfunction in DMD, suggesting that extrasynaptic 
      GABAA receptors might be candidate targets for future therapeutic developments.
CI  - (c) The Author 2017. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Vaillend, Cyrille
AU  - Vaillend C
FAU - Chaussenot, Remi
AU  - Chaussenot R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Dystrophin)
RN  - 0 (Isoxazoles)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (apo-dystrophin 1)
RN  - K1M5RVL18S (gaboxadol)
SB  - IM
MH  - Animals
MH  - Brain/*metabolism/physiopathology
MH  - Cognition/physiology
MH  - Disease Models, Animal
MH  - Dystrophin/*genetics/metabolism
MH  - Fear/physiology
MH  - GABAergic Neurons/*metabolism/pathology
MH  - Humans
MH  - Isoxazoles/administration & dosage
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Muscular Dystrophy, Duchenne/*genetics/physiopathology
MH  - Receptors, GABA-A/genetics/metabolism
MH  - Stress, Psychological/*genetics/physiopathology
EDAT- 2017/01/15 06:00
MHDA- 2017/05/16 06:00
CRDT- 2017/01/15 06:00
PHST- 2016/10/11 00:00 [received]
PHST- 2016/12/30 00:00 [accepted]
PHST- 2017/01/15 06:00 [pubmed]
PHST- 2017/05/16 06:00 [medline]
PHST- 2017/01/15 06:00 [entrez]
AID - ddx013 [pii]
AID - 10.1093/hmg/ddx013 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2017 Mar 15;26(6):1041-1055. doi: 10.1093/hmg/ddx013.