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http://hdl.handle.net/11375/26991
Title: | Astrocyte-mediated purinergic signalling in the Fragile X mouse cortex |
Other Titles: | Purinergic signalling in the Fragile X mouse cortex |
Authors: | Reynolds, Kathryn |
Advisor: | Scott, Angela |
Department: | Neuroscience |
Keywords: | Fragile X syndrome;autism;purinergic signalling;astrocyte;cerebral cortex |
Publication Date: | 2021 |
Abstract: | Disordered communication between cortical neurons and glia underlies many of the characteristics of Fragile X syndrome (FXS), the most common monogenic form of intellectual disability and autism spectrum disorder (ASD). Despite extensive research, no effective treatments exist to comprehensively mitigate ASD- or FXS-related cognitive and motor disabilities, sensory hyperresponsivity, seizures, and other excitation-related symptoms. Glial-glial and glial-neuronal communication can be facilitated by purinergic signalling pathways, which utilize ATP, UTP, and their metabolites to influence both short-term and longer-term activation. The overall objective of this thesis work was to establish whether purinergic signalling is dysregulated within cortical astrocytes derived from the Fmr1 KO mouse model of FXS, and furthermore, to determine whether astrocyte purinergic dysregulations contribute to aberrant Fmr1 KO neuronal-glial interactions. Collectively, these studies provide the first reported evidence that P2Y receptor-driven purinergic signalling is elevated in Fmr1 KO cortical astrocytes, and suggest that this impacts the formation and activity of neuronal circuitry in a manner consistent with FXS symptomatology. Fmr1 KO cortical astrocyte dysregulations included elevated expression of P2Y2 and P2Y6 purinergic receptors, increased intracellular calcium release following P2Y activation, aberrant levels of intracellular purinergic signalling molecules, and increased ectonucleotidase glycosylation. UTP treatment promoted excess Fmr1 KO astrocyte expression and secretion of the synaptogenic protein TSP-1 to potentially influence neuronal connectivity, as well as increased phosphorylation of transcription factor STAT3 to likely drive cortical immune responses. Both exogenous UTP and the presence of Fmr1 KO astrocyte secretions promoted neurite outgrowth, while Fmr1 KO astrocyte-neuron co-cultures demonstrated elevated neuronal burst frequency that was normalized through chronic and selective P2Y2 antagonism. Together, these findings indicate novel and significant astrocyte P2Y-mediated purinergic upregulations within the Fmr1 KO mouse cortex, and suggest that astrocyte purinergic signalling should be further investigated in the search for innovative FXS treatments. |
URI: | http://hdl.handle.net/11375/26991 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Reynolds_Kathryn_E_202109_PhD.pdf | 23.93 MB | Adobe PDF | View/Open |
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