title: N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.
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.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.|School of Medicine, Faculty of Health, Deakin University, Locked Bag 20000, Geelong, Victoria 3220, Australia.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Wright
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia, l.gray@deakin.edu.au.|School of Medicine, Faculty of Health, Deakin University, Locked Bag 20000, Geelong, Victoria 3220, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gray
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.|Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.affiliation: The University of Queensland Centre for Clinical Research, Queensland 4029, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Pow
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.
authors.forename: Terence Y
authors.initials: TY
authors.lastname: Pang
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, Victoria 3220, Australia.
authors.forename: Zoe M
authors.initials: ZM
authors.lastname: Smith
authors.affiliation: Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, Victoria 3220, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Francis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.
authors.forename: Thibault
authors.initials: T
authors.lastname: Renoir
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, Victoria 3010, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D001344:Autopsy; D001522:Behavior, Animal / Q000187:drug effects; D023902:Chromosome Pairing / Q000187:drug effects / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis / Q000235:genetics; D003553:Cystine / Q000096:biosynthesis; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D003553:Cystine; D003542:Cystathionine gamma-Lyase; D000111:Acetylcysteine