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.
Highlights
Neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia affect about 1% of the population (Saha et al, 2005; Baron-Cohen et al, 2009)
This study provided proof-of-concept evidence that glutamate levels and behavior can be altered acutely by extra-synaptic mechanisms targeting glial cells
NAC treatment reduced the prepulse inhibition of startle response in females exclusively
Summary
Neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia affect about 1% of the population (Saha et al, 2005; Baron-Cohen et al, 2009). Their etiology is poorly understood, and treatments are limited. E/I imbalance in neurodevelopmental conditions can arise directly via alteration in genes encoding glutamatergic receptors or synaptic adhesion proteins (Silverman et al, 2012, 2015; Spooren et al, 2012). Abnormalities in the genes encoding these proteins have been reported in both ASD and schizophrenia (Bang and Owczarek, 2013), and animal models have confirmed their role in synaptic transmission and behaviors relevant to neurodevelopmental disorders (Graf et al, 2004; Dahlhaus and El-Husseini, 2010; Grayton et al, 2013)
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