Sunday, March 16, 2025
3/16/2025
Summary Many central neurons release neuromodulatory transmitters, for example monoamines, neuropeptides, and neurotrophins, from their somata and dendrites. Release of these transmitters is followed by G-protein coupled receptor activation, and these neuromodulator pathways are essential for brain development and function. Dopamine signaling in the ventral midbrain is a prominent example of this transmission mode, and it is particularly important for the response to drugs of abuse. The knowledge of somatodendritic release and G-protein coupled receptor-mediated transmission lags far behind that of synaptic signaling, but it is often considered slow and imprecise. The long-term goal of this project is to determine the molecular mechanisms that mediate somatodendritic dopamine transmission. We hypothesize that somatodendritic dopamine secretion is mediated by mechanistically specialized machinery for fast and synchronous release. We propose that this machinery is assembled into release hotspots to generate a signal with rapid kinetics that is directed towards G-protein coupled receptor domains on target cells, an architecture ideally suited for robust receptor activation. Our recent work has made first progress towards this goal. We have found that RIM, a protein important for the spatiotemporal precision of axonal transmitter release, is essential for evoked somatodendritic dopamine release. Furthermore, we found that synaptotagmin-1, a fast Ca2+ sensor, mediates Ca2+-triggering of this form of release. We here propose to determine the organization and function of somatodendritic dopamine release machinery using conditional mouse gene knockout, electrophysiology, imaging and superresolution microscopy. In aim 1, we propose to dissect somatodendritic release site architecture in midbrain dopamine neurons. We will systematically test the necessity and localization of five key active zone protein families that control speed and location of exocytosis at classical synapses. In aim 2, we propose to identify Ca2+ sources and sensors for somatodendritic dopamine release. We will assess conditional mouse mutants that lack Ca2+ channel or Ca2+ sensor proteins for secretory deficits and will assess the localization of the proteins needed for Ca2+-triggering in the somatodendritic compartments. These aims will define mechanisms of Ca2+-triggering and are likely to identify active zone-like release hotspots. Our work will further reveal shared and distinct release mechanisms in somatodendritic and axonal compartments of dopamine neurons. This multi-PI project will advance the understanding of somatodendritic dopamine signaling in the midbrain specifically, and of G-protein coupled receptor-mediated transmission in general. It combines the expertise of the laboratories of John Williams and Pascal Kaeser. In-depth studies of these mechanisms will allow us to derive principles and specifications of these neuronal secretory pathways and may ultimately help advancing treatments for diseases with disrupted dopamine function, for example drug addiction.
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