TY - JOUR TI - The role of serotonergic dysfunction in the etiology of affective disorder in a Huntington’s disease translational mouse model DO - https://doi.org/doi:10.7282/T38P63M2 PY - 2017 AB - Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder that manifests with a triad of psychiatric, cognitive, and motor symptoms. The pathophysiology of the psychiatric symptoms is not well understood but is frequently associated with serotonergic dysfunction in limbic-related circuits in the brain. However, it remains unknown how the serotonergic system is impaired in HD. The primary aim of this thesis is to assess the use of a translational mouse model of HD to better understand the contribution of serotonergic dysfunction in the etiology of affective disorders in the disease, and to assess the use of novel therapeutics for the amelioration of symptoms. I conducted tests to quantify the incidence of affective disorder in mice and observed that the BACHD mouse model displays anxiety-like and depressive-like behaviors, which are the two most common psychiatric symptoms in HD patients. Importantly, I found evidence that the psychiatric symptoms in the BACHD mice develop prior to the onset of motor deficits, similar to HD patients. The similar behavioral phenotype of this mouse model enabled further investigation into the role of serotonergic neurotransmission in HD. With the use of in vivo microdialysis, I quantified serotonergic efflux, which is a product of serotonin release, reuptake, metabolism and receptor binding. Serotonin efflux was reduced in the ventral hippocampus but not the dorsal striatum, suggesting that serotonin efflux is only reduced in the limbic ventral hippocampus and that monoaminergic activity (including dopamine) in the dorsal striatum remains intact. With additional tests, I determined that activation of the 5-HT1A receptor using an agonist has an anxiolytic and potential antidepressant effect in the BACHD mouse model. Acute administration of the selective serotonin reuptake inhibitor ameliorated depressive symptoms in the BACHD mice. The dual antidepressant and anxiolytic effect of activation of the 5-HT1A receptor is suggestive that serotonergic dysfunction in the BACHD mice is a result of impaired communication in postsynaptic targets of the serotonergic system. KW - Neuroscience KW - Huntington's disease LA - eng ER -