Our long-term scientific goal is to gain a mechanistic understanding of synaptic transmission, with a focus on the establishment and regulation of acetylcholine receptors. Rapid cholinergic neurotransmission at muscles and in the brain is via synaptically released acetylcholine (ACh), which binds to and activates ion-channel forming pentameric receptors (AChRs). These receptors are evolutionarily conserved, and invertebrate and vertebrate organisms express large families of AChR subunits, which can form heteromeric or homomeric AChRs. The various receptors exhibit differential sensitivity to drugs (such as the addictive drug nicotine), and the diversity of receptors contributes to neuronal function and drug dependence. One receptor in particular, the homomeric a7 AChR, is associated with autism, anxiety and schizophrenia. The strength of a7-mediated neurotransmission is critically dependent on the localization and density of a7 AChRs;however, how these receptors or any AChRs are delivered to and localized at synapses is still not well understood. The goal of this proposal is to gain a mechanistic understanding of AChR-mediated synaptic signaling by using a genetic approach in Caenorhabditis elegans to identify signaling pathways that contribute to the delivery or function of a7-like AChRs. We previously demonstrated that synaptic currents mediated by ACR-16, a C. elegans a7 homologue, are dependent on CAM-1, a Ror class receptor tyrosine kinase (RTK). We now have preliminary data demonstrating that mutations in three genes encoding proteins that contribute to Wnt-mediated signaling (CWN-2/Wnt, LIN-17/Fzd, and DSH-1/Dvl) phenocopy the behavioral and electrophysiological defects found in cam-1 mutants. In this proposal we test the model that all four proteins contribute to a Wnt-mediated signaling pathway that is required for the delivery, localization or function of synaptic ACR-16 receptors, we elucidate downstream signaling components, and we measure the in vivo dynamics of receptor trafficking. Cholinergic neurotransmission is implicated in nicotine addiction, memory and cognition. Perturbations in a7 AChR regulation and function are thought to contribute to a broad spectrum of neuronal disorders such as autism, anxiety, and schizophrenia, as well as Alzheimer's and Parkinson's diseases. Because many of the gene products important for synaptic transmission are conserved from invertebrates to vertebrates, we predict that what we learn from our studies in C. elegans will have immediate relevance to ongoing studies in the vertebrate nervous system. Thus, our research efforts might ultimately lead to new diagnostic or therapeutic modalities for neuronal disorders associated with defects in cholinergic neurotransmission.
Excitatory neurotransmission is mediated by the neurotransmitter acetylcholine, which binds to specialized receptors and controls the contraction of muscles, the secretion of glands and the workings of the brain;nicotine can partly mimic the action of acetylcholine and is the active ingredient found in cigarette smoke that leads to addiction. Dysfunction of acetylcholine-mediated signaling is implicated in nicotine addiction, memory and cognition, and a broad spectrum of neuronal disorders such as autism, anxiety, schizophrenia, and Alzheimer's and Parkinson's diseases. The goal of this application is to gain a greater mechanistic understanding of the development and regulation of acetylcholine receptors, which ultimately may contribute to the development of new diagnostic and therapeutic modalities for neurological disorders.
|Jensen, Michael; Hoerndli, Frederic J; Brockie, Penelope J et al. (2012) Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system. Cell 149:173-87|