PMID- 21907762
OWN - NLM
STAT- MEDLINE
DCOM- 20120322
LR  - 20231105
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 198
DP  - 2011 Dec 15
TI  - Pathophysiology of Huntington's disease: time-dependent alterations in synaptic 
      and receptor function.
PG  - 252-73
LID - 10.1016/j.neuroscience.2011.08.052 [doi]
AB  - Huntington's disease (HD) is a progressive, fatal neurological condition caused 
      by an expansion of CAG (glutamine) repeats in the coding region of the Huntington 
      gene. To date, there is no cure but great strides have been made to understand 
      pathophysiological mechanisms. In particular, genetic animal models of HD have 
      been instrumental in elucidating the progression of behavioral and physiological 
      alterations, which had not been possible using classic neurotoxin models. Our 
      groups have pioneered the use of transgenic HD mice to examine the excitotoxicity 
      hypothesis of striatal neuronal dysfunction and degeneration, as well as 
      alterations in excitation and inhibition in striatum and cerebral cortex. In this 
      review, we focus on synaptic and receptor alterations of striatal medium-sized 
      spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We 
      demonstrate a complex series of alterations that are region-specific and 
      time-dependent. In particular, many changes are bidirectional depending on the 
      degree of disease progression, that is, early vs. late, and also on the region 
      examined. Early synaptic dysfunction is manifested by dysregulated glutamate 
      release in striatum followed by progressive disconnection between cortex and 
      striatum. The differential effects of altered glutamate release on MSNs 
      originating the direct and indirect pathways is also elucidated, with the 
      unexpected finding that cells of the direct striatal pathway are involved early 
      in the course of the disease. In addition, we review evidence for early 
      N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity 
      of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the 
      alterations in late HD could be compensatory mechanisms designed to cope with 
      early synaptic and receptor dysfunctions. The main findings indicate that HD 
      treatments need to be designed according to the stage of disease progression and 
      should consider regional differences.
CI  - Copyright (c) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Raymond, L A
AU  - Raymond LA
AD  - Department of Psychiatry and Brain Research Centre, University of British 
      Columbia, Vancouver, Canada.
FAU - Andre, V M
AU  - Andre VM
FAU - Cepeda, C
AU  - Cepeda C
FAU - Gladding, C M
AU  - Gladding CM
FAU - Milnerwood, A J
AU  - Milnerwood AJ
FAU - Levine, M S
AU  - Levine MS
LA  - eng
GR  - R01 NS041574/NS/NINDS NIH HHS/United States
GR  - R01 NS041574-10/NS/NINDS NIH HHS/United States
GR  - MOP 12699/CAPMC/CIHR/Canada
GR  - NS41574/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20110827
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Animals
MH  - Corpus Striatum/*pathology
MH  - Disease Models, Animal
MH  - Humans
MH  - Huntington Disease/*pathology/*physiopathology
MH  - Mice
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Synapses/*physiology
MH  - Time Factors
PMC - PMC3221774
MID - NIHMS321948
EDAT- 2011/09/13 06:00
MHDA- 2012/03/23 06:00
CRDT- 2011/09/13 06:00
PHST- 2011/05/25 00:00 [received]
PHST- 2011/07/31 00:00 [revised]
PHST- 2011/08/22 00:00 [accepted]
PHST- 2011/09/13 06:00 [entrez]
PHST- 2011/09/13 06:00 [pubmed]
PHST- 2012/03/23 06:00 [medline]
AID - S0306-4522(11)00994-8 [pii]
AID - 10.1016/j.neuroscience.2011.08.052 [doi]
PST - ppublish
SO  - Neuroscience. 2011 Dec 15;198:252-73. doi: 10.1016/j.neuroscience.2011.08.052. 
      Epub 2011 Aug 27.