Adiponectin Receptor Modulation as a Therapeutic Approach to Fragile X Syndrome

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dc.contributor.authorShkolnikov, Irene
dc.contributor.supervisorChristie, Brian R.
dc.date.accessioned2023-09-06T23:10:59Z
dc.date.available2023-09-06T23:10:59Z
dc.date.copyright2023en_US
dc.date.issued2023-09-06
dc.degree.departmentDivision of Medical Sciencesen_US
dc.degree.levelMaster of Science M.Sc.en_US
dc.description.abstractFragile X Syndrome (FXS) is a leading cause of monogenic autism disorder (ASD) and intellectual disability (ID) caused by CGG trinucleotide repeat expansions in the 5’ untranslated region of the FMR1 gene. Methylation-dependent silencing of the FMR1 gene and abolition of product protein FMRP translates to altered cognitive function in people with FXS. There is no cure and limited therapies for FXS. Abolition of FMRP causes defective protein translation control and cellular energy metabolism which translates to altered AMPA/NMDA ratios and diminished long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) of FMR1 knockout (KO) mice. This provides precedent for cell metabolic modulation as a therapeutic target in FXS. Our work targets the adipocyte derived protein hormone adiponectin, an endogenous modulator of cellular autophagy, as a therapeutic compound for FXS. We evaluate the effect of a chronic 15-day AdipoRon treatment at a dose of 20mg/Kg on hippocampal DG LTP, DG synaptosomal and whole tissue lysis protein, and contextual and social anxiety-like behavior in adult male FMR1 KO mice. We found that (1) AdipoRon has a unique, significant, and genotype-specific effect on anxiety-like behavior and (2) that differences in hippocampal LTP and proteomic signaling may exist but require further investigation. The direct effect of explicit exogenous adiponectin receptor modulation in FXS has not been investigated before. This novel inquiry into the use of AdipoRon as a therapeutic compound for FXS is a starting point, a valuable pilot study for future work, and a novel theoretical conceptualization of the neuroendocrine axis in FXS. This work could help to advance knowledge in the FXS field and contribute to an improved quality of life for patients with FXS and their families.en_US
dc.description.scholarlevelGraduateen_US
dc.identifier.urihttp://hdl.handle.net/1828/15356
dc.languageEnglisheng
dc.language.isoenen_US
dc.rightsAvailable to the World Wide Weben_US
dc.subjectFragile X Syndromeen_US
dc.subjectTherapeuticsen_US
dc.subjectNeuroendocrine Axisen_US
dc.subjectAnimal Model of Autismen_US
dc.subjectSynaptic Plasticityen_US
dc.subjectAdiponectinen_US
dc.subjectMouse Behavioren_US
dc.subjectSignaling Pathwaysen_US
dc.subjectDrug Targetsen_US
dc.subjectFunctional Alterationsen_US
dc.titleAdiponectin Receptor Modulation as a Therapeutic Approach to Fragile X Syndromeen_US
dc.typeThesisen_US

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