Abstract
Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. Finally, we discover that autophagy is downregulated during late striatal postnatal development (P28) in mice with in utero exposure to valproic acid (VPA), an established mouse model of autism spectrum disorder (ASD). VPA-exposed mice also display deficits in striatal neurotransmission and social behavior. Correction of hyperactive mTOR signaling in VPA-exposed mice restores social behavior. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and provide additional evidence that mTOR-dependent signaling pathways represent pathogenic signaling cascades in ASD mouse models that are active during specific postnatal windows.
Highlights
Best characterized in studies of brewer’s yeast, macroautophagy is a degradative process for long-lived proteins and damaged organelles (Ohsumi, 2014)
Neuronal autophagy has been proposed to play a key role in neurodevelopment and autophagic dysfunction may lead to neurodevelopmental disorders and autism spectrum disorders (ASD) (Tang et al, 2014; Dragich et al, 2016; Kim et al, 2017; Yan et al, 2018; Lieberman et al, 2019b)
In this study we address whether autophagic activity is developmentally controlled in the principal neurons of the striatum, a brain region implicated in neurodevelopmental disorders (Fuccillo, 2016)
Summary
Best characterized in studies of brewer’s yeast, macroautophagy (hereafter referred to as autophagy) is a degradative process for long-lived proteins and damaged organelles (Ohsumi, 2014). Autophagy has been recognized as an important cellular process during neuronal development (Shen and Ganetzky, 2009; Tang et al, 2014; Dragich et al, 2016; Stavoe et al, 2016; Kim et al, 2017; Lieberman et al, 2019a). Autophagic dysfunction is observed in humans with neurodevelopmental disorders (Lee et al, 2013; Poultney et al, 2013; Byrne et al, 2016; Hor and Tang, 2018), and mouse models with reduced autophagy display phenotypes implicated in autism spectrum disorders (ASD) (Tang et al, 2014; Kim et al, 2017; Yan et al, 2018). Little is known about the developmental regulation of neuronal autophagy and the possible implications for ASD
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