Activity-dependent processes that modify the strength of synaptic transmission are thought to play a crucial role in the formation of new memories during learning and in the refinement of synaptic connections that occurs during development. In the hippocampus, a region of the brain known to have a crucial role in memory formation, excitatory synapses express a number of different forms of synaptic plasticity. For instance, some patterns of synaptic activity induce a long-lasting enhancement of synaptic transmission known as long-term potentiation (LTP) while different patterns of activity can induce a long-lasting decrease in transmission known as long-term depression (LTD). The synaptic events leading to LTP and LTD induction are well characterized and key components of the signaling pathways responsible for these forms of plasticity have been identified. Little is known, however, about how the signaling pathways responsible for LTP and LTD interact to generate the """"""""rules"""""""" that determine how synaptic strength is modified by different patterns of synaptic activity. In this project we will use synaptic stimulation protocols that mimic endogenous patterns of neural activity in the hippocampus to investigate the cellular and molecular mechanisms that regulate LTP induction at excitatory synapses onto hippocampal pyramidal cells. In particular, we will investigate the role of activity-dependent changes in NMDA-type glutamate receptor function, nitric oxide production, and cAMP signaling in the ability of certain patterns of synaptic stimulation to disrupt the induction of LTP. In addition, we will investigate synaptic transmission and plasticity in transgenic mice with a mutation in the postsynaptic density protein PSD-95, a protein thought to be an important organizer of NMDA receptor-dependent signaling pathways involved in synaptic plasticity. These experiments will provide insights into the cellular and molecular mechanisms controlling forms of synaptic plasticity thought to be involved in learning and memory and may provide insights into how changes in these processes might contribute to the impairment of memory formation that occurs in Alzheimer's disease and during normal aging.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Vuong, Celine K; Wei, Weizheng; Lee, Ji-Ann et al. (2018) Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1. Neuron 98:127-141.e7
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
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
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
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

Showing the most recent 10 out of 21 publications