This work is relevant to both normal aging and pathologies like Alzheimer?s disease, where brain function is impaired due to defective mitochondrial respiration and loss of cellular energy. The long-term goal of this project is to ameliorate neurotransmission defects due to mitochondrial dysfunction, as a way to stop disease progression to later degenerative stages, increasing healthspan in populations increasingly subject to age- related neurological diseases. Fundamental mechanisms underlying the bioenergetics of synaptic function in normal tissue must be resolved first, to cure these diseases. Our goals in this project are two-fold. First, the extent to which mitochondrial Ca2+ uptake facilitates ATP production in response to activity will be defined. Second, the extent that compensatory strategies are utilized at the presynaptic terminal to delay energy loss will be determined when mitochondrial function is impaired. Results from this project will provide clear mechanistic insight into the Ca2+-buffering and ATP-producing roles of synaptic mitochondria, an essential first step that is currently unclear. The PI has developed several novel approaches that allow us to dissect the bioenergetic strategies used to support transmission at the mouse calyx of Held, using a combination of electrophysiology, Ca2+ imaging, and ATP imaging. In contrast to small conventional synapses, giant ?calyx-like? excitatory synapses in the rodent auditory brainstem allow direct whole-cell recordings from the presynaptic terminal. This experimental accessibility permits manipulation of presynaptic [Ca2+] and [ATP], making it possible to dissect the interdependent Ca2+-buffering and energy-supporting roles of synaptic mitochondria. In the first Specific Aim, the extent that the mitochondrial calcium uniporter (MCU) facilitates mitochondrial respiration and ATP homeostasis following synaptic activity will be determined. The second Specific Aim will dissect the importance of mitochondrial Ca2+ uptake versus facilitated respiration on synaptic transmission and presynaptic short-term plasticity. Namely, is the MCU more important for Ca2+ buffering or ATP homeostasis at the synapse? In Specific Aim three, the consequence of metabolic switching between glycolysis and mitochondrial respiration in support of transmission will be examined in normal synapses, and in cases where MCU function is acutely or chronically impaired. This project will provide a detailed understanding of the range of metabolic strategies that are employed by synapses to support synaptic transmission in physiological and pathological settings. This knowledge will identify viable routes of intervention for restoring function to energy-deficient synapses that can be leveraged therapeutically to alleviate disease-related synaptic dysfunction.

Public Health Relevance

The product of this research will immediately provide new, critical, and fundamental knowledge on the routes of energy supply in healthy neuronal synapses, and how synapses compensate for loss of mitochondrial function. This is important, as mitochondrial dysfunction is a core cause of aging and neurodegenerative diseases such as Alzheimer?s Disease. This knowledge will have long-term impact by shaping new hypothesis-based strategies regarding synaptic bioenergetics, which can then be tested and applied therapeutically to alleviate disease- related synaptic dysfunction. The motivation for this project is to enhance healthspan in populations increasingly subject to age-related neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Gubitz, Amelie
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University of Nevada Reno
Schools of Medicine
United States
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