Our Mission
The goal of the Mosca Lab is to provide an environment where science of the highest calibre can be done.
Every member has the right to speak freely and be judged on the quality of their work and their character.
We commit to training students, postdocs, and technicians so they can succeed in any scientific careers.
We are a safe space that values tolerance, collaboration, truth, and support in the pursuit of outstanding science.
The Mosca Lab studies, broadly, how synapse organization arises in the brain and how that organization enables behavior. We study the Drosophila olfactory system, taking in vivo genetic, biochemical, and microscopy approaches to understand the molecular pathways that enable synapses to form and achieve the precise three-dimensional patterns seen in adults (Mosca and Luo, eLife, 2014). We also study how altering synapse organization affects the ability of the fly to smell and respond to attractive and aversive odorants. By connecting molecules with behaviors, we hope to achieve a better understanding of how synaptic organization arises to enable robust behavior.
Cell-Type Specific Synapse Organization
We study how synapses are organized in mature sensory circuits in the pomace fly Drosophila melanogaster. Specifically, we focus on the antennal lobe, the first order processing center for olfactory information in the fly brain, and the correlate to the human olfactory bulb. We pioneered techniques (Mosca and Luo, eLife, 2014) for studying the three-dimensional organization of synapses in the genetically identified neurons at the light level, as in individual classes of olfactory receptor neurons (right). Recent work has identified the developmental maps and mechanisms for central olfactory circuits (Aimino et al. Journal of Neuroscience, 2023) and built new postsynaptic tools (Parisi et al., Cell Reports Methods, 2023) to map circuit organization. Our current work involves using these techniques to map three-dimensional synapse organization in olfactory circuits, identify new cell surface receptors in synaptic development and maintenance, and build new strategies to study synapse organization in vivo.
The mechanisms of synapse development
We have identified a number of genes that regulate synapse formation in the CNS and are working towards understanding how they function. We discovered that the Teneurins, an emerging class of synapse organization molecules, control synapse number by regulating the presynaptic cytoskeleton (Mosca and Luo, eLife, 2014). Recent work has identified LRP4 (Mosca et al., eLife, 2017) as a key presynaptic organizer of excitatory synapses (left). LRP4 functions through the activity of the SR-protein kinase SRPK79D to regulate synapse number and olfactory behavior. Current work is exploring the biochemical mechanisms by which these genes function. Other projects in the lab are studying mutations that regulate synapse development, spacing of active zones (but not number), and synapse size. We combine the genetic advantages of Drosophila with in vivo biochemistry to delve deeper into the molecular mechanisms of synapses.
Circuit Interactions and Behavior
Studying the fly olfactory system allows us to intimately connect synapse organization with robust behavior. Flies use their sense of smell to find food and mates and avoid stressful situations. We want to know how the precise patterns of three-dimensional synapse organization in the antennal lobe and in higher brain centers like the lateral horn (right) enable these behaviors. Why does it matter not just how many connections there are, but WHERE they are as well? Additional projects in the lab seek to decompose the components of synapse organization, using behavior, circuit interaction studies, and functional imaging to determine how each specific aspect of of synapse structure regulates coordinated output of the circuit. By connecting the molecular mechanisms of synapse development with behavior and neuronal function, we seek to achieve a more complete nature of how circuits arise and interact to form a mature sensory system.
Synaptic development and Maturation
Synaptic connections do not function perfectly as soon as they form. After formation, synapses undergo a process of maturation to become robust, reliable connections. They recruit additional postsynaptic proteins and undergo functional changes to optimize function. Failures in maturation can underlie neuropsychiatric, neurodevelopmental, and even neurodegenerative disorders. Our work identified novel roles for postsynaptic γ-secretase in promoting maturation via the Fz2 receptor (Restrepo et al, Developmental Cell, 2022) and presynaptic LRP4 (DePew et al, BioRxiv, 2023) at the Drosophila NMJ. This advanced our understanding of synaptic maturation and its consequences. Critical questions remain, however! Current work is directed at 1) identifying new molecules that regulate synaptic maturaiton, 2) understanding the downstream mechanisms underlying Fz2 / γ-secretase maturation, and 3) determining how neurodegenerative risk genes influence maturation; all with the goal of connecting why failed maturation leads to neurological disorders.