Browsing by Author "Asher, Melissa"

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    Ataxin-1 in cognition and mood
    (2017-11) Asher, Melissa
    Ataxin-1 (ATXN1), the gene mutated in spinocerebellar ataxia type 1 (SCA1), may affect cognition and mood, but much remains unknown, including which brain areas are responsible, whether ATXN1 affects mood in mice, and the mechanisms of these effects. To answer these questions, we characterized cognition and mood in several ATXN1 mutant mouse lines: Atxn1+/- and Atxn1-/- mice to compare 50% and 100% loss of ATXN1; Atxn1154Q/2Q and Atxn178Q/2Q mice to compare SCA1-like polyglutamine expansions of different lengths; and Purkinje cell specific Pcp2-ATXN1[82Q] mice to determine the cerebellar contribution. Atxn1-/- and Atxn1154Q/2Q mice showed cognitive deficits. Reduced hippocampal neurogenesis in Atxn1-/- mice may explain this. Cognition was not affected in Atxn1+/-, Atxn178Q/2Q, or Pcp2-ATXN1[82Q] mice. We also observed mood abnormalities not consistent with depression or anxiety. These results provide a foundation for further research into the function of ataxin-1 and the potential side effects of reducing ataxin-1 levels to treat SCA1.
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    A functional endocannabinoid system in human induced pluripotent stem cell-derived cortical cultures
    (2022-04) Asher, Melissa
    The endocannabinoid system is an increasingly popular therapeutic target in many neurological conditions, due in large part to its ability to protect neurons from damage caused by hyperactivity and excitotoxicity. Despite recent interest in cannabinoid-based treatments, the unavailability of human brain tissue and species differences between humans and animal models present obstacles to drug development. Human induced pluripotent-derived stem cells (hiPSCs), which can be obtained less invasively from skin samples and then reprogrammed into neurons and glia, are one possible solution to this problem. However, it is not clear whether hiPSC-derived neurons actually have a working endocannabinoid system to study. In this thesis I characterize the endocannabinoid system in a commercially available line of hiPSC-derived cortical neuron/astrocyte cultures using calcium imaging and a fluorescent cannabinoid indicator expressed in live neurons. hiPSC-derived cultures produced and metabolized endocannabinoids in addition to responding to exogenously applied cannabinoids, indicating that they do indeed possess a fully functional endocannabinoid system. I also show that endocannabinoid synthesis evoked by a muscarinic receptor agonist in hiPSC-derived cortical cultures is not calcium-dependent, and that an inhibitor of endocannabinoid metabolism produces less receptor desensitization than a cannabinoid receptor agonist with prolonged exposure. These studies demonstrate that hiPSC-derived neuron/astrocyte cultures are a powerful new tool for investigating open questions about the regulation of the human endocannabinoid system.