Understanding the molecular mechanisms and the organizational logic of how synapses are constructed is essential to understanding neurotransmission in the brain. By knowing how connections form, when they form, and the rules they follow in comprising a circuit, we can understand how the brain processes information. By deciphering the genes involved in synapse formation and composition, we can also make great strides in understanding neurodevelopmental and intellectual disabilities.
We combine genetics, state-of-the-art microscopy, biochemistry, and behavioral analysis to understand the links between molecules and function.
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 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). These techniques, based on the active zone protein Bruchpilot, allow us to quantify synapse number and determine their three-dimensional position and organization in an intact circuit (Mosca and Luo, eLife, 2014). Current projects involve using these techniques to map three-dimensional synapse organization in olfactory circuits, study synapse development in early circuits, and developing new tools and techniques to study synapse organization in insects and mice.
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.