Mitochondrial Synthesis of Neurotransmitters in Synaptic Function and Memory

Objective

Released neurotransmitters must be replenished at extraordinarily fast time scales to support synaptic function, circuit physiology and behavior. However, how axonal metabolism responds to the demands of neuronal activity to preserve neurotransmitter levels remains poorly understood. While our understanding of the biochemical pathways for neurotransmitter synthesis is vastly detailed, very little is known about how these pathways are implemented in mammalian axons to preserve synaptic function and behavior. I hypothesize axonal mitochondria sense neuronal activity and boost their metabolism to provide metabolic precursors that locally replenish glutamate and GABA (γ-aminobutyric acid), the main neurotransmitters of the mammalian nervous system. This localized synthesis ensures rapid refilling of activity-emptied synaptic vesicles, thereby safeguarding synaptic strength and brain function. MitoTransmitters aims to reveal a central role for axonal mitochondria in neurotransmitter metabolism, underscoring the importance of mitochondrial physiology beyond the classical bioenergetics. To do so, we will i) combine high-throughput optophysiology measurements of synaptic function together with the development of novel optical sensors for cytosolic glutamate and GABA, defining the metabolic pathways preserving synaptic function in excitatory and inhibitory neurons. We will also ii) integrate these findings at the behavioral level by developing novel optogenetic activators of mitochondrial metabolism and examining the role of mitochondrial neurotransmitter synthesis in long-term memory in rodents. By generating for the first time a comprehensive picture of the molecular mechanisms actively preserving neurotransmitter levels, this study will provide a theoretical and experimental framework for future studies into the molecular basis of brain disease states associated with dysfunctional metabolism, such as mitochondriopathies or neurodegenerative disorders.