Our long-term scientific goals have been to gain a mechanistic understanding of synaptic transmission mediated by the neurotransmitter glutamate. Neurotransmission is critically dependent on excitatory synaptic signaling mediated by AMPA-class ionotropic postsynaptic glutamate receptors (AMPARs). Experience- dependent changes in the properties and numbers of AMPARs are considered to be of central importance for learning and memory. Recent studies have demonstrated that the function of AMPARs is severely impaired in the absence of auxiliary proteins, raising fundamental new questions about how the AMPAR complex functions and how it is transported to synapses. Using a genetic approach in C. elegans, we have established that the GLR-1 AMPA subtype of iGluR (AMPAR) is part of a multi-protein receptor complex and that its function depends on auxiliary proteins from two distinct classes of transmembrane proteins. One class is related to vertebrate TARP proteins and contains the proteins STG-1 and STG-2, the other contains a CUB-domain single-pass transmembrane protein, SOL-1. Our preliminary studies for modifiers of AMPAR function have now identified SOL-2, a single-pass transmembrane protein with CUB domains that we hypothesize contributes to the AMPAR complex. In the absence of SOL-2, AMPAR-mediated current is greatly diminished. In this proposal, we aim to address three fundamental questions: 1) Where is SOL-2 expressed and does it associate with AMPARs? 2) How does SOL-2 contribute to glutamatergic signaling and synaptic transmission? 3) How are components of the AMPAR complex transported to distant synaptic sites? Our specific aims address two critical issues in synaptic biology: 1) What proteins contribute to the AMPAR complex and how do they function, and 2) How are the components of the complex transported to distant synaptic sites? Using reconstitution studies and electrophysiological measurements of in vivo synaptic activity, we will determine the role of SOL-2 in AMPAR-mediated glutamate-gated currents, synaptic signaling and behavior. The transport of AMPARs is still not well understood, and estimates of the rate of transport differ by over an order of magnitude. In addition, no studies have examined the transport of the essential AMPAR auxiliary proteins. We propose to study transport of these components in vivo. Our studies will test the hypothesis that the transport of GLR-1 and other components of the AMPAR complex is mediated by specific motor proteins. These studies are motivated by our preliminary results which show that GLR-1 transport is differentially disrupted in mutants predicted to disrupt kinesin-mediated and dynein-mediated transport. Together, our proposed studies will provide a mechanistic understanding of the transport and function of AMPARs. Thus, our research efforts might eventually contribute to the development of new diagnostic and therapeutic modalities for neurological disorders such as Alzheimer's disease, Parkinson's disease, and stroke.

Public Health Relevance

Most neurotransmission in the brain is dependent on synapses that release glutamate and activate AMPARs. Thus, it is no wonder that dysfunction or overexcitation of AMPARs is associated with many acute and chronic neurological disorders including developmental and mental health disorders, excitotoxicity and stroke syndromes, and degenerative diseases such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis (ALS). The aims of this proposal are to gain a greater mechanistic understanding of transport and function of AMPARs, which ultimately may contribute to the development of new diagnostic and therapeutic modalities for neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-N (02))
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Silberberg, Shai D
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Hoerndli, Frédéric J; Wang, Rui; Mellem, Jerry E et al. (2015) Neuronal Activity and CaMKII Regulate Kinesin-Mediated Transport of Synaptic AMPARs. Neuron 86:457-74
Hoerndli, Frédéric J; Kallarackal, Angy J; Maricq, Andres V (2015) Mobile AMPARs are required for synaptic plasticity. Channels (Austin) 9:230-2
Brockie, Penelope J; Jensen, Michael; Mellem, Jerry E et al. (2013) Cornichons control ER export of AMPA receptors to regulate synaptic excitability. Neuron 80:129-42
Hoerndli, Frédéric J; Maxfield, Dane A; Brockie, Penelope J et al. (2013) Kinesin-1 regulates synaptic strength by mediating the delivery, removal, and redistribution of AMPA receptors. Neuron 80:1421-37
Wang, Rui; Mellem, Jerry E; Jensen, Michael et al. (2012) The SOL-2/Neto auxiliary protein modulates the function of AMPA-subtype ionotropic glutamate receptors. Neuron 75:838-50
Spooner, Patrick M; Bonner, Jennifer; Maricq, Andres V et al. (2012) Large isoforms of UNC-89 (obscurin) are required for muscle cell architecture and optimal calcium release in Caenorhabditis elegans. PLoS One 7:e40182
Brockie, Penelope J; Maricq, Andres V (2010) In a pickle: is cornichon just relish or part of the main dish? Neuron 68:1017-9
Stetak, Attila; Hörndli, Frederic; Maricq, Andres V et al. (2009) Neuron-specific regulation of associative learning and memory by MAGI-1 in C. elegans. PLoS One 4:e6019
Wang, Rui; Walker, Craig S; Brockie, Penelope J et al. (2008) Evolutionary conserved role for TARPs in the gating of glutamate receptors and tuning of synaptic function. Neuron 59:997-1008
Kano, Takashi; Brockie, Penelope J; Sassa, Toshihiro et al. (2008) Memory in Caenorhabditis elegans is mediated by NMDA-type ionotropic glutamate receptors. Curr Biol 18:1010-5

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