The focus of my laboratory's work is to understand the mechanisms by which neurons form synaptic connections, how synapses transmit information, and how synapses change during learning and memory. To complement this basic research in neuroscience, we also study how alterations in neuronal signaling underlie several neurological diseases, including epilepsy, autism and Huntington’s Disease. We combine molecular biology, protein biochemistry, electrophysiology, and imaging approaches with Drosophila genetics to address these questions. Moving beyond genomic data to determine how proteins specify the distinctive signaling properties of neurons and enable them to interconnect into computational circuits that dictate behavior are major goals in neuroscience research. Despite the dramatic differences in complexity between Drosophila and humans, genomic analysis has confirmed that key neuronal proteins and the functional mechanisms they govern are remarkably similar. As such, we are attempting to elucidate the mechanisms underlying synapse formation, function and plasticity using Drosophila as a model system. By characterizing how neurons integrate synaptic signals and modulate synaptic growth and strength, we hope to bridge the gap between molecular components of the synapse and the physiological responses they mediate.
We are developing new toolkits that allow us to image both synaptic transmission and synapse formation in real time in living animals using the Drosophila model. This research direction is allowing unprecedented access to experimental approaches to dissect acutely how synapses form and how they function. We are defining how individual active zone release sites work and how they can be modified during synaptic plasticity. We have also discovered a new pathway of signaling between glia and neurons that holds great potential to define how glia can acutely control neuronal activity in the brain, and how dysregulation of this pathway may contribute to epilepsy. Finally, we are also using these tools to discover how neurological disorders like autism may disrupt these key structural and functional signaling networks at synapses.
Our research during the last year has revealed new insights into how synaptic connections form and function to transmit information within the brain. We have characterized the role of several key proteins, including synaptotagmin, complexin and synaptogyrin that form the molecular machinery that allows the presynaptic side of the synapse to release neurotransmitters and initiate neuronal signaling in the brain. We have also used Drosophila as a genetic system to model Huntington’s Disease (HD), an adult-onset neurodegenerative disorder resulting from an expansion of a polyglutamine (polyQ) track within the Huntingtin (Htt) protein. We have generated Drosophila HD transgenic models expressing fluorescently tagged wildtype and pathogenic Htt proteins that allow for in vivo imaging of Htt localization, axonal transport and aggregate formation in live animals. We have identified several pathologies associated with Htt polyQ expression in fly neurons, and have identified small molecules and genetic interactors that can revert HD pathology in our system. We are also studying mutants of the Drosophila Htt homolog to define the normal function of Htt within neurons. Together, these approaches have advanced our understanding of HD pathophysiology and provided new insights into how synapses normally mediate communication between neurons.
Troy Littleton received his MD and Ph.D. from Baylor College of Medicine in Houston, TX. He completed his postdoctoral training at the University of Wisconsin. In 2000, he joined the faculty of the Department of Biology and the Picower Institute for Learning and Memory at MIT.
Weiss, K.R., Kimura, Y., Lee, W.M. & Littleton, J.T. (2012) Huntingtin aggregation kinetics and their pathological role in a Drosophila Huntington’s Disease Model. Genetics 190, 581-600.
Jorquera, R.A., Huntwork-Rodriguez, S., Akbergenova, Y., Cho, R.W. & Littleton, J.T. (2012) Complexin controls spontaneous and evoked neurotransmitter release by regulating the timing and properties of Synaptotagmin activity. J. Neuroscience 32, 18234-18245.
Stevens, R., Akbergenova, Y., Jorquera, R.A. & Littleton, J.T. (2012) Abnormal synaptic vesicle biogenesis in Drosophila synaptogyrin mutants. J. Neuroscience 32, 18054-18067.
Buhl, L.K., Jorquera, R.A., Akbergenova, Y., Huntwork-Rodriguez, S., Volfson, D. & Littleton, J.T. (2013) Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of Complexin. Mol. Cell. Neuroscience 52, 161-172.
Lee, J., Guan, Z., Akbergenova, Y. & Littleton, J.T. (2013) Genetic analysis of Synaptotagmin C2 domain specificity in regulating spontaneous and evoked neurotransmitter release. J. Neuroscience 33, 187-200.
Melom, J.E. & Littleton, J.T. (2013) Mutation of a NCKX eliminates glial microdomain calcium oscillations and enhances seizure susceptibility. J. Neuroscience 33, 1169-1178.
Poitras Scholar Award in Neuroscience
Alfred P. Sloan Research Fellow
Human Frontier Science Program Junior Faculty Fellowship
Searle Scholar Award
Surdna Research Foundation Award
Wade Fund Award
David and Lucile Packard Foundation Fellowship for Science and Engineering
Fred and Carole Middleton Career Development Professorship
Member, Faculty of 1000
Distinguished Alumni Award, Baylor College of Medicine