N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.
Article Details
- CitationCopy to clipboard
Wright DJ, Gray LJ, Finkelstein DI, Crouch PJ, Pow D, Pang TY, Li S, Smith ZM, Francis PS, Renoir T, Hannan AJ
N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.
Hum Mol Genet. 2016 Jul 15;25(14):2923-2933. doi: 10.1093/hmg/ddw144. Epub 2016 May 14.
- PubMed ID
- 27179791 [ View in PubMed]
- 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-gamma-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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Acetylcysteine Glutamate receptor ionotropic, NMDA 1 Protein Humans UnknownActivatorDetails Acetylcysteine Glutamate receptor ionotropic, NMDA 2A Protein Humans UnknownActivatorDetails Acetylcysteine Glutamate receptor ionotropic, NMDA 2B Protein Humans UnknownActivatorDetails Acetylcysteine Glutamate receptor ionotropic, NMDA 2D Protein Humans UnknownActivatorDetails Acetylcysteine Glutamate receptor ionotropic, NMDA 3A Protein Humans UnknownActivatorDetails