The execution of complex functions and their breakdown in disease involves the interplay between an animal's genetics and environment. The overall goals of this proposal are to reveal how Ras-family GTPases influence signaling networks that control synaptic plasticity, and how an """"""""enriched environment"""""""" (EE) alters these networks to change the way synaptic plasticity is induced in adolescent mice and remarkably, across generations. One focus of this proposal is on GRF1 and GRF2, which form a family of multi-catalytic, calcium- stimulated, guanine nucleotide exchange factors that have the potential to activate both Ras and Rac GTPases. Despite these similarities, we found that GRF1 and GRF2 promote opposing forms of synaptic plasticity induced by NMDA-type glutamate receptors (NMDA-Rs) beginning at early adolescence. GRF1 promotes long-term depression (LTD), while GRF2 promotes long-term potentiation (LTP), at least in part, because they regulate different MAP kinases. The experiments outlined below combine genetic, biochemical and electrophysiological studies to reveal how GRF1 and GRF2 respond to different upstream signals, and how signaling downstream from their Ras- and Rac-activating domains is differentially regulated in the hippocampus. These experiments will add new insight into how specificity is achieved in neuronal signal transduction. They will also add significantly to our understanding of the molecular basis of LTP and LTD induction. Defects in these well-established cellular paradigms of learning and memory are thought to contribute to a variety of neurological and mental health disorders. A second focus of this proposal is how environmental stimulation, involving exposure to novel objects, enhanced socialization and voluntary exercise particularly during pre-adolescence, changes the way LTP is induced. We discovered that adolescent enrichment unlocks a previously unidentified latent signaling pathway that promotes LTP in mice and rescues defective LTP and contextual fear memory in GRF knockout mice. Even more dramatic is our finding that these effects of pre-adolescent enrichment are passed on to the next generation through their adolescence. The experiments described will use multiple approaches to reveal how this novel EE-gated signaling pathway promotes LTP, and how EE unlocks this cascade to affect synaptic plasticity and memory across generations. A better understanding of the trans-generational effects of the environment on brain function may reveal new approaches to overcome neurological and mental health disorders.

Public Health Relevance

Although a person's genetic blueprint strongly contributes to his/her susceptibility to disease, it is clear that the environment in which one lives influences how that blueprint is read. Our study investigates how Ras proteins contribute to biochemical pathways in the brain that mediate learning and memory. It also explores how a stimulating enriched environment, particularly during pre-adolescence, changes these biochemical pathways in normal animals, and compensates for a genetic defect in Ras signaling. Remarkably, we find that juvenile enrichment affects not only animals directly exposed to it, but also their future offspring through adolescence. A full understanding of the trans-generational effects of the environment on brain function may reveal new approaches to overcome neurological and mental health disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Asanuma, Chiiko
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Tufts University
Schools of Medicine
United States
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Uzturk, Belkis Gizem; Jin, Shan-Xue; Rubin, Beverly et al. (2015) RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early-adolescent female mice. J Endocrinol 227:1-12
Darcy, M J; Jin, S-X; Feig, L A (2014) R-Ras contributes to LTP and contextual discrimination. Neuroscience 277:334-42
Darcy, Michael J; Trouche, St├ęphanie; Jin, Shan-Xue et al. (2014) Ras-GRF2 mediates long-term potentiation, survival, and response to an enriched environment of newborn neurons in the hippocampus. Hippocampus 24:1317-29
Jin, Shan-Xue; Bartolome, Christopher; Arai, Junko A et al. (2014) Domain contributions to signaling specificity differences between Ras-guanine nucleotide releasing factor (Ras-GRF) 1 and Ras-GRF2. J Biol Chem 289:16551-64
Darcy, Michael J; Trouche, St├ęphanie; Jin, Shan-Xue et al. (2014) Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus. Hippocampus 24:315-25
Jin, Shan-Xue; Arai, Junko; Tian, Xuejun et al. (2013) Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP). J Biol Chem 288:21703-13
Saavedra-Rodriguez, Lorena; Feig, Larry A (2013) Chronic social instability induces anxiety and defective social interactions across generations. Biol Psychiatry 73:44-53
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Arai, Junko A; Feig, Larry A (2011) Long-lasting and transgenerational effects of an environmental enrichment on memory formation. Brain Res Bull 85:30-5
Sowalsky, A G; Alt-Holland, A; Shamis, Y et al. (2010) RalA suppresses early stages of Ras-induced squamous cell carcinoma progression. Oncogene 29:45-55

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