Nervous systems are plastic, that is, they can change with experience allowing us to learn, remember and forget. Experience-dependent plasticity occurs in part at synapses - specialized points of contact that mediate signaling between neurons. Experiences, sensations and emotions strengthen or weaken these connections shaping how the nervous system processes and stores information. Our long-term scientific goal is to uncover the molecular machinery that controls synaptic plasticity, as well as to understand how components of this machinery are assembled, and delivered to and regulated at synapses. The AMPA subtypes of ionotropic glutamate receptors (AMPARs) mediate synaptic transmission at most excitatory synapses. We have developed new genetic strategies to uncover the molecular machinery required for synaptic transmission at glutamatergic synapses in C. elegans. In a series of studies, we identified four classes of evolutionarily conserved auxiliary subunits that contribute to AMPAR function, showed that they have dramatic effects on in vivo glutamate-gated currents, and demonstrated that mutations in these genes predictably modify AMPAR-mediated behaviors. We also discovered that the delivery and removal of synaptic AMPARs was dependent on kinesin-1 microtubule-dependent motors. Thus, AMPAR transport along neuronal processes, and glutamate-gated currents, are dramatically reduced in unc-116 mutants (KIF5) and klc-2 mutants (Kinesin light chain 2). These findings led us to search for signaling molecules that regulate the transport of AMPARs. We have now identified two classes of evolutionarily conserved kinases that contribute to the transport of AMPARs to synapses. These same kinases are implicated in cellular models of learning and memory, such as long-term potentiation and long-term depression. We now plan to test the hypothesis that these kinase-signaling pathways contribute to the regulated delivery of synaptic AMPARs and their auxiliary proteins. We predict that what we learn from our proposed studies will have immediate relevance to ongoing studies of synaptic plasticity, learning and memory in vertebrates. Thus, our studies could contribute to new diagnostic or therapeutic modalities for disorders associated with altered neurotransmission in the brain.

Public Health Relevance

The goal of our research is to identify and characterize the molecular machinery that contributes to synaptic signaling in the nervous system, with a focus on signaling mediated by the neurotransmitter glutamate. Our immediate goal is to gain an understanding of the molecular mechanisms that regulate motor-driven transport of glutamate receptors in neurons, and how these processes contribute to synaptic plasticity, learning and memory. Synaptic function depends on motor-driven transport and is often compromised in neurodegenerative disorders, thus our studies might ultimately contribute to the development of new diagnostic and therapeutic modalities for the treatment of neurological and psychiatric disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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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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