Parkinson's Disease (PD) is the most common neurodegenerative movement disorder. Historically, PD has been considered a strictly neuronal disease; however, clinical observations and evidence from animal models suggest inflammation may contribute to disease progression. It remains controversial whether glial activation, and the resulting inflammatory cascade, is a result or a cause of neuronal death. Towards resolving this distinction, I established cultures of human embryonic stem cell derived dopaminergic neurons, and primary human astrocytes and microglia. These neural cells are used to investigate the glial inflammatory response to extracellular insults, and the neuronal response to pro- inflammatory mediators. I established that these cells are a robust model of neuro-inflammation, found that the glial derived pro-inflammatory response can be serially propagated between astrocytes and microglia following a single inflammatory insult, and that glial derived inflammatory factors are neurotoxic. Using these assays, I identified the anti-inflammatory and neuro-protective effects of flavonoid apigenin, an inducer of orphan nuclear receptor Nurr1, whose dual role as both neuro- protective and anti-inflammatory renders it an ideal target for therapeutic intervention in PD. The purpose of this project is to elucidate the role of inflammation in PD and identify key molecular events involved at early stages in PD to exploit as potential targets for therapeutic intervention. These results are important because they establish an in vitro model that enables investigation into the inflammatory contribution to the pathological development of PD, and identification of novel therapeutic compounds

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.