PMID- 24603212
OWN - NLM
STAT- MEDLINE
DCOM- 20150413
LR  - 20140704
IS  - 1878-5832 (Electronic)
IS  - 1359-6446 (Linking)
VI  - 19
IP  - 7
DP  - 2014 Jul
TI  - Mechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease.
PG  - 990-6
LID - S1359-6446(14)00058-0 [pii]
LID - 10.1016/j.drudis.2014.02.006 [doi]
AB  - Huntington's disease (HD) is an inherited neurodegenerative disorder of movement, 
      mood and cognition, caused by a polyglutamine expansion in the huntingtin (Htt) 
      protein. Genetic mouse models of HD, along with improved imaging techniques in 
      humans at risk of, or affected by, HD, have advanced understanding of the 
      cellular and/or molecular mechanisms underlying its pathogenesis. The striatum 
      begins to degenerate before other brain areas, and altered activity at 
      corticostriatal synapses contributes to an imbalance in survival versus death 
      signaling pathways in this brain region. Striatal projection neurons of the 
      indirect pathway are most vulnerable, and their dysfunction contributes to motor 
      symptoms at early stages of the disease. Mutant Htt expression changes striatal 
      excitatory synaptic activity by decreasing glutamate uptake and increasing 
      signaling at N-methyl-d-aspartate receptors (NMDAR). A variety of studies 
      indicate that reduced brain-derived neurotrophic factor (BDNF) transcription, 
      transport and signaling contribute importantly to striatal neuronal dysfunction 
      and degeneration in HD. Striatal dopamine and endocannabinoid signaling are also 
      altered and progressively become dysfunctional. Changes at striatal neurons vary 
      with the stage of disease and clinical symptoms. Therapeutics targeting multiple 
      neurotransmitter signaling systems could support physiological synaptic function 
      and delay disease onset.
CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
FAU - Sepers, Marja D
AU  - Sepers MD
AD  - Department of Psychiatry and Brain Research Centre, University of British 
      Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
FAU - Raymond, Lynn A
AU  - Raymond LA
AD  - Department of Psychiatry and Brain Research Centre, University of British 
      Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: 
      lynn.raymond@ubc.ca.
LA  - eng
GR  - GPG 102165/Canadian Institutes of Health Research/Canada
GR  - MOP-12699/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20140303
PL  - England
TA  - Drug Discov Today
JT  - Drug discovery today
JID - 9604391
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Corpus Striatum/metabolism/pathology
MH  - Dopamine/metabolism
MH  - Glutamic Acid/metabolism
MH  - Humans
MH  - Huntington Disease/*metabolism/*pathology
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Signal Transduction/physiology
MH  - Synapses/*metabolism/*pathology
EDAT- 2014/03/08 06:00
MHDA- 2015/04/14 06:00
CRDT- 2014/03/08 06:00
PHST- 2014/02/20 00:00 [received]
PHST- 2014/02/24 00:00 [accepted]
PHST- 2014/03/08 06:00 [entrez]
PHST- 2014/03/08 06:00 [pubmed]
PHST- 2015/04/14 06:00 [medline]
AID - S1359-6446(14)00058-0 [pii]
AID - 10.1016/j.drudis.2014.02.006 [doi]
PST - ppublish
SO  - Drug Discov Today. 2014 Jul;19(7):990-6. doi: 10.1016/j.drudis.2014.02.006. Epub 
      2014 Mar 3.