Appropriate regulation of synaptic strength is essential for maintaining stability in neural circuits. This regulation hinges on a balance between molecular mechanisms that promote change in synaptic function in response to extracellular and intracellular cues, and homeostatic mechanisms that seek to adjust neuronal function within a normal range, ensuring stability in neural circuits circuits1-2. This proposal is designed to unravel molecular components and mechanisms that contribute to homeostatic mechanisms at the synapse. My group has been taking advantage of the Drosophila larval neuromuscular junction (NMJ) as a model synapse. When postsynaptic function is reduced at this synapse, a robust homeostatic retrograde signal is initiated in the postsynaptic muscles, which feeds back to the presynaptic motor neuron to cause a compensatory enhancement in presynaptic neurotransmitter release1. The NMJ is a particularly well-suited model for studying this feedback or retrograde signaling mechanism, since the short life cycle of flies together with the powerful genetics available in Drosophila allow for an efficient identification and characterizatio of genes and mechanisms that participate in this coordinated process. In particular, our recently published work3 as well a wealth of unpublished preliminary findings indicate that translational mechanism that control do novo protein synthesis are essential for the ability of the NMJ to induce this retrograde compensation in neurotransmitter release. In addition, we have strong preliminary data that a Parkinson's related genes interacts with translational mechanisms and thereby influences synaptic transmission at the NMJ. We have also identified potential translational targets for postsynaptic translation that may further shed light into the nature of tis signaling. Our research plan is based on a wealth of preliminary data and unpublished observations and utilizes a multidisciplinary approach that combines Drosophila genetics with molecular biology, biochemistry, imaging and electrophysiology. We have a unique opportunity for understanding how retrograde signaling operates at synapses to induce homeostatic effects. In light of the highly conserved nature of these signaling molecules, our findings hold the promise of being translated to higher organisms and pave the way for future therapeutic approaches aimed at tackling nervous system diseases.

Public Health Relevance

It has been recognized for some time that the stability of neuronal activity in the nervous system hinges on a coordinated action of different molecular mechanisms that respond to changes in synaptic activity. We provide evidence that de novo protein synthesis, in response to changes in synaptic activity in the target cell, leads to the generation of a signaling cascade that feeds back to the nerve terminals to regulate the level of neurotransmitter release. Our proposed studies are designed to extend our understanding of how this form of communication in the nervous system is regulated and how it might be influenced by a Parkinson's related gene, thus providing new potential avenues for tackling this devastating disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Gubitz, Amelie
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Buck Institute for Age Research
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Kauwe, Grant; Tsurudome, Kazuya; Penney, Jay et al. (2016) Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism. Neuron 92:1204-1212
Penney, Jay; Tsurudome, Kazuya; Liao, Edward H et al. (2016) LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nat Commun 7:12188