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)
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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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
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
Mellem, Jerry E; Brockie, Penelope J; Madsen, David M et al. (2008) Action potentials contribute to neuronal signaling in C. elegans. Nat Neurosci 11:865-7
Walker, Craig S; Brockie, Penelope J; Madsen, David M et al. (2006) Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc Natl Acad Sci U S A 103:10781-6
Zheng, Yi; Brockie, Penelope J; Mellem, Jerry E et al. (2006) SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc Natl Acad Sci U S A 103:1100-5
Walker, Craig S; Francis, Michael M; Brockie, Penelope J et al. (2006) Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc Natl Acad Sci U S A 103:10787-92
Norman, Kenneth R; Fazzio, Robert T; Mellem, Jerry E et al. (2005) The Rho/Rac-family guanine nucleotide exchange factor VAV-1 regulates rhythmic behaviors in C. elegans. Cell 123:119-32
Hills, Thomas; Brockie, Penelope J; Maricq, Andres V (2004) Dopamine and glutamate control area-restricted search behavior in Caenorhabditis elegans. J Neurosci 24:1217-25
Grunwald, Maria E; Mellem, Jerry E; Strutz, Nathalie et al. (2004) Clathrin-mediated endocytosis is required for compensatory regulation of GLR-1 glutamate receptors after activity blockade. Proc Natl Acad Sci U S A 101:3190-5

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