All aspects of memory, behavior, and cognition rely on the synaptic connections between neurons. To begin to understand neural function, the synapses themselves must first be understood: how are they organized, what are the molecular mechanisms necessary for their development and function, and how do synapses from one type of neuron interact with the synapses from other neuronal classes? This proposal aims to address these questions by determining the organization of synapses in the central brain of Drosophila melanogaster, the molecules necessary for their maintenance and development, and how synapses of different neurons interact. In the Drosophila olfactory system, three neuronal classes cooperate to enable robust sensing of odors from the environment, processing of these odors, and transmission of the information to higher brain centers. The olfactory system thus represents an opportunity to study a genetically accessible system with single-cell resolution and stereotypy within single neurons or between groups of neurons. I have developed methods to study synapse organization in the olfactory system, establishing a new model central synapse. These methods have revealed new aspects of synaptic organization in olfactory neurons in the Drosophila antennal lobe. This proposal will further this work, providing a high-resolution analysis of synapses in single olfactory neurons. It will determine when these synapses develop and how the developing synapse differs from that of the mature olfactory neuron. Such analyses will provide an essential framework from which to address how pathological conditions, including neurodevelopmental disorders, can alter synapse organization. Further, I will use this new model synapse to examine three classes of molecules, the Teneurins, Neurexins and Neuroligins, which are linked to intellectual disabilities and autism spectrum disorders. Understanding how each of these entities contributes to synapse organization is essential for gaining insight into the bases of these disorders. Finally, I will investigate how the synapses of different neurons within a circuit are interrelated. Coordination among neurons in a circuit is essential for its function and organismal behavior. But how a circuit achieves this coordination on a synaptic level is largely unknown. Using newly established methods, I will ask how perturbing the synapses of one neuronal class within a circuit affect synapses of the other neurons. Specifically, I will determine how a circuit deals wih synapse increase and reduction in one specific type, and how chemical synapses within a circuit respond to the loss of electrical synapses. Further study of the mechanisms underlying these circuit responses will unveil new molecules and organizational paradigms responsible for their construction. By understanding these aspects of organization for individual synapses and between groups of synapses, we will gain considerable insight into not just neuronal function, but into how a neural circuit coordinates information to ensure proper function at the organism level.

Public Health Relevance

Neurons are connected by synapses, which are the fundamental units of function in the brain. Understanding their organization;how they signal, how they organize, how they contribute to memory formation, and how they allow behavioral response;is an essential prerequisite to determining how neurological disorders and intellectual disabilities like autism can arise. My research seeks to understand these connections, where they form, how they form, when they form, and how genes contribute to their normal function.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Career Transition Award (K99)
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Communication Disorders Review Committee (CDRC)
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Sklare, Dan
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Stanford University
Schools of Arts and Sciences
United States
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Mosca, Timothy J; Luginbuhl, David J; Wang, Irving E et al. (2017) Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons. Elife 6:
Sakuma, Chisako; Saito, Yoshie; Umehara, Tomoki et al. (2016) The Strip-Hippo Pathway Regulates Synaptic Terminal Formation by Modulating Actin Organization at the Drosophila Neuromuscular Synapses. Cell Rep 16:2289-97
Mosca, Timothy J (2015) On the Teneurin track: a new synaptic organization molecule emerges. Front Cell Neurosci 9:204
Mosca, Timothy J; Luo, Liqun (2014) Synaptic organization of the Drosophila antennal lobe and its regulation by the Teneurins. Elife 3:e03726