Troy Littleton
Using the fly model Drosophila, Professor Troy Littleton's lab studies the connections (synapses) that link together neurons within the brain. The lab is focused on understanding how neurons form synaptic connections, how those connections work to transmit information, and how the connections change during learning and memory. The lab is also exploring the mechanisms underlying two human brain disorders: epilepsy and Huntington's disease.
The computational power of the brain depends on precise connections ("synapses") that link together billions of neurons. The focus of my laboratory's work is to understand the mechanisms by which neurons form synaptic connections, how those connections work to transmit information, and how the connections 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, "Fragile X" mental retardation and Huntington's Disease.
With the completion of several animal genome sequences, neurobiologists are now able to examine the complete set of neuronal and synaptic proteins that govern brain function. Major goals for the next decade: interpreting this wealth of sequence data to understand how proteins specify the distinctive signaling properties of neurons and enable them to interconnect into computational circuits that dictate behavior.
As a model system for our studies, we use the fruit fly, Drosophila melanogaster. 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. With these similarities in mind, we are attempting to elucidate the molecular mechanisms underlying synapse formation, function and plasticity. By characterizing how neurons are capable of integrating synaptic signals and modulating synaptic growth and strength, we hope to bridge the gap between the molecular components of the synapse and the physiological responses they mediate. We combine molecular biology, protein biochemistry, microarray technology, electrophysiology, and imaging approaches with Drosophila genetics to investigate neuronal signaling. These studies will provide important insights into how the nervous system functions at the cellular level, allowing us to integrate this information into the framework of our goal of ultimately understanding how neuronal ensembles mediate behavior, and how human neurological diseases disrupt these processes.
To understand how neurons form synapses, we have used genetic approaches to remove or disrupt proteins essential to the process. We have identified several neuronal pathways that control synapse formation and synaptic growth. We have found that the influx of calcium during brain activity plays an important modulatory role in triggering the morphological changes that mediate synapse growth. Several effectors of synaptic growth that we have identified include proteins that modulate the assembly/disassembly of the neuronal cytoskeleton, as well as the activity of the cAMP pathway that functions during learning and memory.
Neurons at the receiving end of synapses also contribute to establishing connections. We have shown that abolishing neurotransmitter signals received by the postsynaptic neuron leads to defective connections. Synapse formation requires the receiving neuron to transmit information back to the input neuron via retrograde signaling pathways.
To complement these studies on synapse formation, we also study how synaptic connections function following assembly. Together with other laboratories, we have identified a molecular machinery that functions to sense calcium rises in nerve terminals during brain activity and trigger information transfer between neurons. Finally, we have identified ~200 candidate "plasticity genes" whose expression are differentially regulated by brain activity and that may contribute to cellular forms of behavioral plasticity, providing molecular clues into how the brain changes during learning and memory.
With the realization that many basic neuronal mechanisms are conserved between Drosophila and humans, we have also used Drosophila to model several devastating neurological diseases. Huntington's Disease is an inherited neurodegenerative disorder that leads to cognitive defects, motor abnormalities and premature death by age 30 to 40. Recently, the mutated gene product that causes Huntington's Disease has been identified, but its function, as well as potential therapeutic approaches to the disease, are still a mystery. We have expressed the mutated human gene in Drosophila and reproduced many aspects of the neurological damage that occurs in humans. We are now studying how the mutant Huntington protein causes toxicity and how it can be prevented. We hope that finding ways to cure our Drosophila model of Huntington's Disease will reveal conserved mechanisms that might be eventual targets for therapy in humans.
Additional strategies are being used to generate and characterize Drosophila models of epilepsy, Alzheimer's Disease, "Fragile X" mental retardation and muscular dystrophy. Together with our basic neuroscience research, these studies will expand our understanding of the mechanisms of synapse formation, function and plasticity. They will also provide insights into changes in brain function that allow neuronal ensembles to store information and into how those processes become dysfunctional in neurological disease.
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