Single-Vesicle\nElectrochemistry in Fresh Brain Slices\nEnables In Situ Quantification of Vesicular Monoamine

The\nquantitative analysis of vesicular neurotransmitters in neurons\nin situ is paramount for investigating neurodegenerative disorders,\nsuch as Alzheimer’s disease and Parkinson’s disease\n(PD). Unfortunately, a direct approach for monitoring neurotransmitter\nchemistry in single vesicles in fresh brain tissue has remained inaccessible\nso far. Here, we introduce an innovative platform of single-vesicle\nelectrochemistry (SVE) in fresh brain tissue, enabling the quantification\nof neurotransmitters at the single-vesicle level for both soma and\nvaricosity. Utilizing this methodology, we investigated a PD animal\nmodel, which demonstrated a significant reduction in both vesicular\ndopamine (DA) storage and exocytotic release in DA neurons in the\nsubstantia nigra. Furthermore, SVE unveiled the heterogeneous nature\nof chemical neurotransmission among DA neurons across different brain\nregions. Importantly, this tissue-based SVE approach can be extended\nto quantify other monoamine neurotransmitters, such as norepinephrine\nand serotonin, at the single-vesicle level. The introduction of this\nmethodology marks a significant advancement, offering a novel avenue\nto explore neurological and psychiatric disorders through the lens\nof neurotransmitter signaling in the mammalian brain. This breakthrough\nhas the potential to deepen our understanding of the underlying mechanisms\nof these complex disorders and may pave the way for the development\nof targeted therapeutic interventions.