Mitochondria Exhibit Changes in Morphology/Function to Support Increased Glutamate Release in TauP301L Neurons Prior to Reduction in Presynaptic Vesicle Release

We have shown that tauopathy models display early-stage hyperexcitability due to increased presynaptic glutamate release that is mediated by an increase in vesicular glutamate transporter-1 (VGlut1). This hyperexcitability increases energy demand which in turn would increase demand on mitochondria. It is unclear, however, how early-stage presynaptic changes in glutamate release are supported by or influence the function of mitochondria. Using Large Area Scanning Electron Microscopy (LA-SEM) and fluorescence microscopy, we demonstrate that mitochondrial changes in morphology, structure, and function in CA1/CA3 hippocampal neurons decrease resting mitochondrial membrane potential in P301L mice. However, P301L mitochondria maintain a high membrane potential during levels of high activity, suggesting that they can support increased energy demand during hyperexcitability. These activity-dependent differences in membrane potential can be rescued by inhibiting ATP-dependent VGlut1 vesicle refilling. This indicates that the increased VGlut1 per vesicle observed in P301L mice contributes to the differences in mitochondria membrane potential. Notably, the mitochondrial dysfunction in P301L mice occurs before any observable alterations in presynaptic release mechanics, suggesting these changes may represent early therapeutic targets. Finally, we propose a model of increased glutamate-mediated changes in mitochondrial morphology and function in P301L neurons that represents a potentially targetable pathway to reduce or arrest neurodegeneration. ### Competing Interest Statement The authors have declared no competing interest.