title: Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.
abstract: An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
authors.forename: Alice M S
authors.initials: AM
authors.lastname: Durieux
authors.affiliation: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
authors.forename: Declan
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Physiology and Behaviour Laboratory, Swiss Federal Institute of Technology Schwerzenbach, Switzerland.
authors.forename: Marie Anais
authors.initials: MA
authors.lastname: Labouesse
authors.affiliation: Physiology and Behaviour Laboratory, Swiss Federal Institute of Technology Schwerzenbach, Switzerland ; Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse Zurich, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Giovanoli
authors.affiliation: Physiology and Behaviour Laboratory, Swiss Federal Institute of Technology Schwerzenbach, Switzerland ; Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse Zurich, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong Hong Kong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
authors.forename: Po-Wah
authors.initials: PW
authors.lastname: So
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
authors.forename: Grainne
authors.initials: G
authors.lastname: McAlonan
keywords: N-acetylcysteine; anxiety; glutamate; magnetic resonance spectroscopy; neurodevelopmental disorders; prepulse inhibition