N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease

Wright, Dean J., Gray, Laura J., Finkelstein, David I., Crouch, Peter J., Pow, David, Pang, Terence Y., Li, Shanshan, Smith, Zoe M., Francis, Paul S., Renoir, Thibault and Hannan, Anthony J. (2016) N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease. Human Molecular Genetics, 25 14: 2923-2933. doi:10.1093/hmg/ddw144

Author Wright, Dean J.
Gray, Laura J.
Finkelstein, David I.
Crouch, Peter J.
Pow, David
Pang, Terence Y.
Li, Shanshan
Smith, Zoe M.
Francis, Paul S.
Renoir, Thibault
Hannan, Anthony J.
Title N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2016-07-15
Sub-type Article (original research)
DOI 10.1093/hmg/ddw144
Open Access Status Not yet assessed
Volume 25
Issue 14
Start page 2923
End page 2933
Total pages 11
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2017
Language eng
Formatted abstract
Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington’s disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc-. In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system xc- and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system xc- and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders.
Keyword Antidepressive agents
Huntington's disease
Depressive disorders
Membrane transport proteins
Glutamate receptor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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