Autism spectrum disorders (ASDs) are a diverse class of neurodevelopmental disorders with various aberrant cellular phenotypes such as dysfunctional neurotransmission and irregular neuronal morphology. ASDs have a broad underlying genetic background with many genes linked to their etiology. UBE3A has been identified as a top gene candidate associated with ASD, and overexpression of UBE3A via copy-number variation confers hallmark ASD behaviors in humans and transgenic mice. Our previous work revealed that synapse formation was negatively affected in the Ube3A-ASD mouse model (Ube3A 2X Tg, or simply “2X Tg”). However, the cellular and molecular mechanisms underlying the synaptic dysregulation remain unknown. We sought to identify a cell-type specific mechanism by which these morphological changes were conferred. We found that selective overexpression of Ube3A in neurons failed to induce changes in dendritic spine maturation. In contrast, overexpression of Ube3A in astrocytes resulted in alterations in spines and synapses. Further, we
identified thrombospondin-2 (TSP2), a secreted astrocytic glycoprotein promoting synaptogenesis and spinogenesis, is involved in the defective spine maturation. Ube3A overexpression confers a loss of transcriptional down-regulation of TSP2 in astrocytes, and the medium of astrocyte cultures with Ube3A overexpression was sufficient to trigger spine changes similar to that observed in mixed cultures that globally overexpress Ube3A. Importantly, depletion of TSP2 promoted similar loss of dendritic spine maturation, whereas supplement of TSP2 to 2X Tg astrocyte media was able to rescue the spine defects. Furthermore, overexpression of Ube3A in an astrocyte-specific manner recapitulated aberrant dendritic spine maturation as well as autism-like behaviors displayed in 2X Tg mice. Collectively, these findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46375 |
| Date | 17 June 2023 |
| Creators | Gardner, Zachary V. |
| Contributors | Man, Hengye |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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