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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, vol. 25, no. 14, pp. 2923-2933, doi: 10.1093/hmg/ddw144.

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Title N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease
Author(s) 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.ORCID iD for Francis, Paul S. orcid.org/0000-0003-4165-6922
Renoir, Thibault
Hannan, Anthony J.
Journal name Human molecular genetics
Volume number 25
Issue number 14
Start page 2923
End page 2933
Total pages 11
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 2016
ISSN 1460-2083
Summary 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.
Language eng
DOI 10.1093/hmg/ddw144
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085626

Document type: Journal Article
Collections: School of Medicine
School of Life and Environmental Sciences
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Created: Tue, 23 Aug 2016, 14:46:48 EST

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