Aberrant Serotonergic Morphology in the Central Nervous System of Drosophila

For years the neurotransmitter serotonin has been recognized as an important developmental signal in addition to its role as a modulator in the mature nervous system. Evidence also indicates that serotonin is capable of autoregulation of serotonergic morphology by fine-tuning the arborization of serotonergic projections. Therefore alterations in serotonin levels may greatly impact serotonergic homeostasis and lead to physical aberrations in brain morphology. Such aberrations are now beginning to be linked to complex disorders such as autism, depression, and anxiety. This dissertation focuses on the effect of excess serotonin production on the morphology of serotonergic neurons in Drosophila, a well-characterized model system for the study of the serotonergic system. Utilizing high-resolution imaging techniques in conjunction with genetic and pharmacological manipulations the following studies identify and characterize dystrophic serotonergic neurites induced by excess serotonin production. Due to similar serotonergic morphologies reported in neurodegenerative disease and following drug administration, the cellular mechanisms responsible for altered morphology in the fly were investigated. Data indicates that increased cytoplasmic serotonin levels cause formation of neuritic swellings, or spheroids, that can be cleared through autophagic mechanisms and may represent protein aggregates. Functional assays suggest that these spheroids confer protection in locomotor abilities. Replication of druginduced serotonergic dystrophy in mice highlights similarities between aberrant morphologies in the fly and mouse. A plausible mechanism linking elevated cytoplasmic serotonin and intracellular signaling is also discussed. This dissertation was completed under the direction of Barry G. Condron, Ph.D., Department of Biology.

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