The small GTPase protein Ras is important for many neuronal processes essential to synaptic plasticity including long-term synaptic potentiation, formation of new synapses, and regulation of cell excitability. Ras is also important for protein synthesis and gene transcription required for long-term maintenance of synaptic plasticity. Consistent with essential roles of Ras signaling in synaptic plasticity, abnormal Ras signaling is associated with diseases causing cognitive impairments and learning deficits. Although the importance of Ras signaling in synaptic plasticity is well recognized, it is not clear how the spatiotemporal dynamics of Ras signaling regulate its diverse downstream effects in different subcellular compartments. Using 2-photon fluorescence lifetime imaging and 2-photon glutamate uncaging, the objective of this project is to elucidate mechanisms and roles of Ras activation in neurons during synaptic plasticity induced in a single dendritic spine.
Our specific aims are 1) to elucidate the roles of Neurofibromin in shaping the spatiotemporal profile of Ras activation in single spines, 2) to determine the activation kinetics of kinases that controls Ras activation during spine structural plasticity, and 3) to elucidate the mechanisms of synapse to nucleus Ras-ERK signaling. This work will advance our understanding of how Ras couples calcium with synaptic plasticity, and ultimately with learning and memory.

Public Health Relevance

Synaptic plasticity is regulated by signaling mediated by Ras. Many forms of learning disabilities and other mental diseases are caused by abnormal Ras signaling. Our proposed research will improve our knowledge of the biochemical events that underlie Ras signaling and its role in synaptic plasticity and learning and memory, and will hopefully provide significant impact on the therapeutics of Ras-related learning disability and other mental diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Asanuma, Chiiko
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Max Planck Florida Corporation
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Oliveira, Ana F; Yasuda, Ryohei (2014) Neurofibromin is the major ras inactivator in dendritic spines. J Neurosci 34:776-83
Kim, Il Hwan; Wang, Hong; Soderling, Scott H et al. (2014) Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall. Elife 3:
Colgan, Lesley A; Yasuda, Ryohei (2014) Plasticity of dendritic spines: subcompartmentalization of signaling. Annu Rev Physiol 76:365-85
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Oliveira, Ana F; Yasuda, Ryohei (2013) An improved Ras sensor for highly sensitive and quantitative FRET-FLIM imaging. PLoS One 8:e52874
Murakoshi, Hideji; Wang, Hong; Yasuda, Ryohei (2011) Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472:100-4
Patterson, Michael; Yasuda, Ryohei (2011) Signalling pathways underlying structural plasticity of dendritic spines. Br J Pharmacol 163:1626-38
Yasuda, Ryohei; Murakoshi, Hideji (2011) The mechanisms underlying the spatial spreading of signaling activity. Curr Opin Neurobiol 21:313-21
Ramsey, Amy J; Milenkovic, Marija; Oliveira, Ana F et al. (2011) Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner. Proc Natl Acad Sci U S A 108:5795-800
Lee, Ming-Chia; Yasuda, Ryohei; Ehlers, Michael D (2010) Metaplasticity at single glutamatergic synapses. Neuron 66:859-70

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