Targeting Glia with N-Acetylcysteine Modulates Excitation/Inhibition Balance, Neural Activity and Rescues Behavioural Deficits in BTBR Mice

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
A. Durieux1, M. M. Petrinovic2, M. D. Saxe2, M. von Kienlin3, D. G. Murphy4, B. K√ľnnecke5 and G. M. McAlonan6, (1)Kings College London, London, United Kingdom, (2)F. Hoffmann-La Roche, Basel, Switzerland, (3)2Roche Pharma Research & Early Development, Neuroscience, Roche Innovation Center, Basel, Switzerland, (4)Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences,, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, (5)Neuroscience, Roche Pharma Research & Early Development, Neuroscience, Roche Innovation Center, Basel, Switzerland, (6)Department of Forensic and Neurodevelopmental Science, IoPPN, KCL, London, United Kingdom

Although the causal mechanisms of autism spectrum disorder (ASD) are poorly understood, recent advances suggest that an imbalance between excitatory (E) glutamate and inhibitory (I) GABA neurotransmission is a prominent feature of the condition and may be contribute to social impairments and repetitive behaviours.  Targeting E/I balance pharmacologically may therefore be a promising approach for drug discovery in ASD. Multiple factors converge to modulate E/I balance in vivo, including synaptic and glial mechanisms. For instance, ASD is associated with synaptic gene anomalies that directly disrupt glutamate and GABA signalling; however increasing evidence suggests that glial dysfunction also contributes to E/I imbalance in ASD. N-acetylcysteine (NAC), an FDA approved mucolytic drug which has shown some clinical benefits to treat severe stereotypies in ASD, is thought to modulate glutamate levels through activation of the cystine-glutamate antiporter located on glia. 


In this study we tested the hypothesis that acute administration of NAC alters E/I balance, and causes related changes in neural activity patterns and behaviour in BTBR mice, an inbred strain which exhibits behavioural and neuro-morphological phenotypes reminiscent of ASD. 

Methods:  By combining translational neuroimaging modalities, i.e., perfusion-based functional magnetic resonance imaging (fMRI) and quantitative spectroscopy (MRS), with behavioural assessments we  investigated the effects of acute NAC treatment on social and repetitive behaviours, as well as their underlying neurochemistry and circuitry in BTBR and control C57BL/6J mice.

Results:  Striatal activity and glutamate levels were elevated in BTBR mice, whereas basal neural activity in the mPFC was comparable with that of C57BL/6J mice. BTBR mice also exhibited severe stereotypies and reduced social interactions, as documented previously. Acute NAC treatment reduced cortical glutamate in both strains, though this was not significant in BTBR mice. NAC normalised abnormal repetitive behaviours as well as social interaction duration in BTBR mice, while concomitantly decreasing striatal neural activity to control levels. Similar modulation of neural activity and decrease in stereotypies were also observed in C57BL/6J mice. Notably, locomotor activity was not affected by NAC. 


NAC treatment normalises social and repetitive behaviour in BTBR mice, likely through modulation of E/I balance which has functional consequences on corticostriatal circuitry. This provides evidence that pharmacological modulation of glial mechanisms can shift E/I balance acutely, with associated neuro-functional and behavioural consequences. Glial metabolism may be a potential drug target for the development of new therapies for ASD. Additionally, our findings warrant further investigation into the potential therapeutic use of NAC in individuals with ASD.

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See more of: Animal Models