Genetic access to synaptic mechanisms of memory in the behaving animal - Axo-axonal synaptic integration in control of neurotransmitter release

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This Emmy Noether project focuses on understanding the synaptic mechanisms of appetitive memory storage within the mushroom bodies (MBs) of the model organism Drosophila at an axo-dendritic synaptic junction (Owald et al., 2015; Perisse, Owald et al., 2016; Barnstedt, Owald et al., 2016). As a key result of this project, we were able to identify a novel mechanism of postsynaptic memory storage involving nicotinic acetylcholine receptors (Pribbenow et al., manuscript attached). While we have come to a good understanding of memory-storage mechanisms, how novel and learnt information are instantaneously integrated remains largely unclear. The here proposed project now builds on the discovery of an axo-axonal synaptic motif that we uncovered one synapse downstream of memory storage sites (unpublished). Functionality of this connection relies on signaling through the alpha7 nicotinic receptor that has also been identified in presynaptic signaling in vertebrates. Importantly, alpha7 nicotinic receptor knock-down interfered with behavioral programs and altered neurophysiological properties of individual boutons along the same axonal branch. Molecularly, our data suggest that alpha7 subunits can directly interact with proteins of the synaptic vesicle release machinery. We thus hypothesize that alpha7 can shape neurotransmitter release in parallel to canonical pathways via voltage-gated calcium channels. Because we uncovered a similar motif within a network signaling sleep pressure in this Emmy Noether project (Raccuglia et al., 2019), we follow the hypothesis that alpha7-signalling at axo-axonal connections represents a general motif for network integration.Here, we will investigate the molecular structure of axo-axonal contacts utilizing flies harboring GFP-tagged endogenous alpha7 that we constructed in this project. In parallel, we will investigate neurophysiological principles of axo-axonal signaling in the context of olfactory and visual integration of MB output neurons and R5 ring neurons respectively, interrogating subsequent steps of neurotransmitter release using optical sensors. Together, this project aims at structurally (molecularly) and functionally investigating a novel synaptic motif potentially capable of partaking in information integration and instant decision making.