It is becoming clear that autism spectrum disorder (ASD) likely occurs due to dysfunction of developing synapses and synaptic remodeling. Tuberous sclerosis complex (TSC) is a monogenetic disease with a high incidence of ASD. To obtain a deeper understanding of the underlying pathogenic mechanisms of ASD, we propose to take advantage of a TSC mouse model, which is missing the Tsc1 gene only in the cerebellar Purkinje cells (PCs). These conditional TSC mutant mice exhibit the common core characteristics of ASD: lack of interest in socializing, repetitive behaviors, and cognitive inflexibility. Importantly, Tsc1-deficient PCs display increased spine density, a phenotype previously reported in patients with neurodevelopmental disorders; however the neuronal and non- neuronal mechanisms that contribute this process remain elusive. In this project, we will investigate two complimentary mechanisms that contribute to the synaptic and behavioral phenotypes in this newly developed TSC mouse model of ASD.
In Aim 1, we will test the hypothesis that impaired autophagy, driven by excess mTOR signaling, prevents normal synaptic remodeling and leads to the increased dendritic spine density on PCs, which contribute to the behavioral abnormalities found in the PC-Tsc1 CKO mice. We will characterize the rate of autophagy including autophagy of mitochondria (mitophagy), and modulate autophagy pharmacologically to test whether we can improve the spine and behavioral phenotypes.
In Aim 2, we turn to cell-extrinsic mechanisms and ask whether the interaction between mutant PCs and microglia, resident immune cells and key mediators of synaptic remodeling, contributes to the spine and ASD-like phenotypes. We hypothesize that Tsc1-deficient Purkinje cells lead to early disruption in microglia development and function, including their ability to prune and signal to synapses. Moreover, our preliminary findings suggest that microglia activation and inflammatory signaling further contribute to synaptic and ASD like phenotypes. We are uniquely positioned to explore the spatio-temporal relationship of microglia changes relative to Tsc1-null PCs using a combination of novel transcriptional profiling (single cell Drop-Seq), and functional assays. We will perform the first detailed transcriptional analysis of microglia and neurons from TSC patients and compare these data with mouse models. Finally, we will determine whether specific manipulation of autophagy and microglia dysfunction in PC-TSC cKO mice rescue synaptic and specific ASD- relevant behaviors. We will leverage four IDDRC cores (Cellular Imaging, Molecular Genetics, Neurodevelopmental Behavior and Clinical Translational Cores) and complimentary expertise of co-PIs, Sahin and Stevens and IDDRC collaborators. Together, these experiments will shed light on the cell intrinsic and extrinsic mechanisms mediating synaptic modeling and may inform new therapeutic targets and biomarkers for TSC and related neurodevelopmental disorders.
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