Activity-dependent processes that persistently modify the strength of synaptic transmission are thought to have a crucial role in the formation of new memories during learning. In the hippocampus, a region of the brain known to have an important role in memory formation, excitatory synapses are capable of undergoing both long-term potentiation (LTP), a long-lasting increase in synaptic strength, as well as long-term depression (LTD), a persistent decrease in the strength of synaptic transmission. Although induced by very different patterns of synaptic activity, the induction of both LTP and LTD is dependent on activation of NMDA-type glutamate receptors. Importantly, NMDA receptors and many of the intracellular signaling pathways involved in plasticity are organized into multi-protein complexes by a family of scaffolding or adaptor proteins known as membrane-associated guanylate kinases (MAGUKs). Although this suggests that MAGUKs are responsible for the formation of NMDA receptor signaling complexes that enable rapid and selective activation of downstream signaling pathways underlying LTP and LTD, little is known about the specific roles these proteins have in LTP and LTD. In this project we will investigate synaptic transmission and plasticity in mice with mutations in MAGUKs that associate with NMDA receptors (SAP102, PSD-93, and PSD-95) to examine the role of these proteins in LTP and LTD. In addition, we will investigate the role of MAGUKs and other signaling molecules in NMDA receptor-dependent activation of the extracellular signal-regulated kinase pathway, a signaling pathway known to have a key role in LTP and learning. These experiments will provide fundamental insights into the molecular mechanisms underlying activity-dependent forms of synaptic plasticity. Moreover, mutations in the gene for the MAGUK SAP102 have recently been identified as a cause of nonsyndromic X-linked mental retardation. Thus, our studies of synaptic transmission and plasticity in SAP102 mutants will not only provide important insights into the roles of MAGUKs in activity-dependent forms of synaptic plasticity but will also identify potential changes in synaptic function that contribute to learning impairments in this form of metal retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060919-10
Application #
7799685
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
1999-12-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
10
Fiscal Year
2010
Total Cost
$245,319
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Chen, Patrick B; Kawaguchi, Riki; Blum, Charles et al. (2017) Mapping Gene Expression in Excitatory Neurons during Hippocampal Late-Phase Long-Term Potentiation. Front Mol Neurosci 10:39
Babiec, Walter E; Jami, Shekib A; Guglietta, Ryan et al. (2017) Differential Regulation of NMDA Receptor-Mediated Transmission by SK Channels Underlies Dorsal-Ventral Differences in Dynamics of Schaffer Collateral Synaptic Function. J Neurosci 37:1950-1964
Fontes, Mariana M; Guvenek, Aysegul; Kawaguchi, Riki et al. (2017) Activity-Dependent Regulation of Alternative Cleavage and Polyadenylation During Hippocampal Long-Term Potentiation. Sci Rep 7:17377
Frank, René A W; Komiyama, Noboru H; Ryan, Tomás J et al. (2016) NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation. Nat Commun 7:11264
Babiec, Walter E; Guglietta, Ryan; O'Dell, Thomas J (2016) Basal levels of AMPA receptor GluA1 subunit phosphorylation at threonine 840 and serine 845 in hippocampal neurons. Learn Mem 23:127-33
O'Dell, Thomas J; Connor, Steven A; Guglietta, Ryan et al. (2015) ?-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn Mem 22:461-71
Gray, Erin E; Guglietta, Ryan; Khakh, Baljit S et al. (2014) Inhibitory interactions between phosphorylation sites in the C terminus of ?-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunits. J Biol Chem 289:14600-11
Babiec, Walter E; Guglietta, Ryan; Jami, Shekib A et al. (2014) Ionotropic NMDA receptor signaling is required for the induction of long-term depression in the mouse hippocampal CA1 region. J Neurosci 34:5285-90
Ryan, Tomás J; Kopanitsa, Maksym V; Indersmitten, Tim et al. (2013) Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nat Neurosci 16:25-32
Coba, Marcelo P; Komiyama, Noboru H; Nithianantharajah, Jess et al. (2012) TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J Neurosci 32:13987-99

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