Skewing information flow through pre- and postsynaptic plasticity in the mushroom bodies of Drosophila

Abstract

Animal brains need to store information to construct a representation of their environment. Knowledge of what happened in the past allows both vertebrates and invertebrates to predict future outcomes by recalling previous experience. Although invertebrate and vertebrate brains share common principles at the molecular, cellular, and circuit-architectural levels, there are also obvious differences as exemplified by the use of acetylcholine versus glutamate as the considered main excitatory neurotransmitters in the respective central nervous systems. Nonetheless, across central nervous systems, synaptic plasticity is thought to be a main substrate for memory storage. Therefore, how brain circuits and synaptic contacts change following learning is of fundamental interest for understanding brain computations tied to behavior in any animal. Recent progress has been made in understanding such plastic changes following olfactory associative learning in the mushroom bodies (MBs) of Drosophila A current framework of memory-guided behavioral selection is based on the MB skew model, in which antagonistic synaptic pathways are selectively changed in strength. Here, we review insights into plasticity at dedicated Drosophila MB output pathways and update what is known about the plasticity of both pre- and postsynaptic compartments of Drosophila MB neurons.

Figure 1.

Overview of pre- and postsynaptic plasticity pathways at the KC–MBON synapse. Memory-relevant synaptic plasticity involves presynaptic KCs, postsynaptic MBONs and DANs. At the presynapse, the Rut-AC and Dunce regulate cAMP levels, which have been proposed to be involved in coincidence detection. The Rut-AC also activates the heme oxygenase which in turn leads to a CO production in KCs required for CO-dependent on-demand dopamine release from DANs (Ueno et al. 2017, 2020; Saitoe et al. 2022). Increase in cAMP levels, moreover, leads to PKA activation in KCs (Gervasi et al. 2010) following pairing of dopamine injection and KC depolarization (Tomchik and Davis 2009). One of the downstream targets of PKA might be Synapsin, which is required for certain memory phases (Knapek et al. 2010). At the Drosophila neuromuscular junction, Synapsin is required both for synaptic vesicle pool size and vesicle release and might have the same function in KCs (Akbergenova and Bykhovskaia 2010) following dopaminergic stimulation (Krüttner et al. 2015). ORB2 forms amyloid-like oligomers (Majumdar et al. 2012) in KCs. ORB2 further interacts with Tob to form oligomers. This oligmomerization is enhanced by the Lim kinase (White-Grindley et al. 2014). ORB2 regulates the synthesis of CAMKII (Krüttner et al. 2015), which autophosphorilates under CASK control (Malik and Hodge 2014). CAMKII regulates axonal growth at the NMJ and therefore potentially also in KCs (Nesler et al. 2016). Additionally, it is required for associative memories in KCs (Chen et al. 2022). Active zone proteins, including the calcium channel Cacophony, the scaffolds BRP, Syd-1, and Spinophilin, and the release factor Unc13 as well as the synaptic vesicle protein Synapsin, have been found to be required for different memory phases (Böhme et al. 2019; Turrel et al. 2022; Ramesh et al. 2023). On the postsynaptic side, the nAChR subunits α2 and α5 are required for appetitive learning. While the α5 subunit shows no sign of memory-related rearrangements, α2 subunit dynamics can be modified. Both the α5 subunit and Dlg, furthermore, seem to act upstream of α2 subunit-containing nAChRs (Pribbenow et al. 2022).