Mitochondrial Fission in Neuronal Function and Models of Alzheimer's Disease

Mitochondria play critical roles in neurons, supporting energy levels and processes, such as neural transmission. Indeed, a breakdown of mitochondrial function may underlie neurodegenerative disease and synaptic degeneration. The process of mitochondrial fission is thought to be particularly important for maintaining mitochondrial health and function. However, the requirement and roles of fission in neuronal populations is unknown. In this thesis, we investigate synaptic energy and the role of mitochondrial fission in neurons. Using newly developed assays, we employ fluorescent probes to simultaneously measure synaptic ATP levels and synaptic vesicle cycling, showing that the endocytotic step is the most energy-demanding. Additionally, we demonstrate a requirement for the key fission protein dynamin-related protein 1 (Drp1) in the hippocampus, a critical learning and memory center of the brain, using a knockout model. We further show that neurons lacking Drp1 have an intrinsic deficit in mitochondrial respiration, specifically at the axon. Finally, we identify novel functions of Drp1 in maintaining ER-mitochondrial contacts and calcium dynamics, a necessity enhanced in the presence of the Alzheimer’s protein amyloid precursor protein. Together, these studies further characterize the energetic requirements at the synapse and the neuronal requirements for Drp1 physiologically and in the context of models of AD