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Title: Neurochemistry in autism spectrum disorder : a translational approach
Author: Durieux, Alice Marie Sybille
ISNI:       0000 0004 6347 9661
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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The pathogenesis of autism spectrum disorder (ASD) may include dysfunction of brain Redox homeostasis and abnormalities in the balance between neuronal excitation (E) and inhibition (I). Both systems have therefore been put forward as potential treatment targets for the development of new pharmacotherapies for the condition. However, ASD is a highly heterogeneous disorder, and it is unclear whether altered oxidative metabolism and/or E/I imbalance occur in all individuals with ASD. Therefore in the first part of this thesis (Study 1), I examined markers of Redox metabolism in a cohort of adult males with ASD already known to have E/I anomalies. Next, I undertook a series of preclinical studies (Studies 2- 4) to investigate whether pharmacological modulation of Redox and/or E/I alters neurochemistry and behaviour in mouse models of ASD. I used in vivo proton magnetic resonance spectroscopy ([1H]MRS) to quantify glutathione (GSH - the major endogenous antioxidant), as a marker of Redox metabolism; and glutamate and GABA (respectively the major excitatory and inhibitory neurotransmitters), as markers of E/I balance. In Study 1, I found GSH was unaltered in adult males with ASD already known to have glutamatergic anomalies. Therefore, my preclinical work focussed upon the regulation of E/I balance. Because the role of glia in E/I and ASD is under-explored, I examined modulation of glutamate by glial mechanisms. In Study 2, I provided proof-of-concept evidence that N-Acetylcysteine (NAC), a compound that activates the cystine-glutamate antiporter of glial cells, reduces glutamate in wild-type C57BL/6J mice. I then sought to translate this finding to a mouse model of ASD with baseline E/I imbalance. After finding that mice lacking synaptic protein Neurexin 1α, a genetic model of ASD, have normal levels of striatal glutamate (Study 3), I excluded this model and instead administered NAC to BTBR mice, an inbred strain with a behavioural phenotype reminiscent of ASD (Study 4). I found that BTBR mice have a baseline E/I imbalance in the striatum and the prefrontal cortex, two brain regions involved in the core symptoms of ASD. These anomalies were partially normalised by NAC treatment, which also improved social interactions and repetitive digging, two behaviours relevant to the core symptoms of ASD. My results suggest that the glial regulatory mechanisms of E/I balance can be modulated pharmacologically, and have consequences for behaviours relevant to ASD. While my preclinical results suggest that the clinical utility of NAC in ASD deserves further exploration, the broader implications of my work are that glial cells are a potential target for the development of new treatments for ASD.
Supervisor: McAlonan, Grainne Mary ; So, Po-Wah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available