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Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease.

Murmu, Reena LU ; Li, Wen LU ; Holtmaat, Anthony and Li, Jia-Yi LU (2013) In Journal of Neuroscience 33(32). p.12997-13009
Abstract
In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long-term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of... (More)
In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long-term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of HD (R6/2) as the disease progressed. In vivo imaging over a period of 6 weeks revealed a steady decrease in the density and survival of dendritic spines on cortical neurons of R6/2 mice compared with control littermates. Interestingly, we also observed increased spine formation in R6/2 mice throughout the disease. However, the probability that newly formed spines stabilized and transformed into persistent spines was greatly reduced compared with controls. In cultured neurons we found that mutant huntingtin causes a loss, in particular of mature spines. Furthermore, in R6/2 mice, aggregates of mutant huntingtin associate with dendritic spines. Alterations in dendritic spine dynamics, survival, and density in R6/2 mice were evident before the onset of motor symptoms, suggesting that decreased stability of the cortical synaptic circuitry underlies the early symptoms in HD. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Neuroscience
volume
33
issue
32
pages
12997 - 13009
publisher
Society for Neuroscience
external identifiers
  • wos:000322823300011
  • pmid:23926255
  • scopus:84881148047
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.5284-12.2013
language
English
LU publication?
yes
id
18315ab3-736e-4d1c-ac4b-388ca37cdb1c (old id 4006025)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23926255?dopt=Abstract
date added to LUP
2013-09-03 14:55:20
date last changed
2019-08-07 01:35:08
@article{18315ab3-736e-4d1c-ac4b-388ca37cdb1c,
  abstract     = {In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long-term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of HD (R6/2) as the disease progressed. In vivo imaging over a period of 6 weeks revealed a steady decrease in the density and survival of dendritic spines on cortical neurons of R6/2 mice compared with control littermates. Interestingly, we also observed increased spine formation in R6/2 mice throughout the disease. However, the probability that newly formed spines stabilized and transformed into persistent spines was greatly reduced compared with controls. In cultured neurons we found that mutant huntingtin causes a loss, in particular of mature spines. Furthermore, in R6/2 mice, aggregates of mutant huntingtin associate with dendritic spines. Alterations in dendritic spine dynamics, survival, and density in R6/2 mice were evident before the onset of motor symptoms, suggesting that decreased stability of the cortical synaptic circuitry underlies the early symptoms in HD.},
  author       = {Murmu, Reena and Li, Wen and Holtmaat, Anthony and Li, Jia-Yi},
  issn         = {1529-2401},
  language     = {eng},
  number       = {32},
  pages        = {12997--13009},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease.},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.5284-12.2013},
  volume       = {33},
  year         = {2013},
}