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The Journal of Neuroscience, February 8, 2006, 26(6):1721-1729; doi:10.1523/JNEUROSCI.3990-05.2006

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Development/Plasticity/Repair
Distinct Roles for Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Ras-GRF2 in the Induction of Long-Term Potentiation and Long-Term Depression

Shaomin Li,^1 * Xuejun Tian,^1 * Dean M. Hartley,² and Larry A. Feig¹

¹Departments of Biochemistry and Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, and ²Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Larry A. Feig, Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. Email: larry.feig{at}tufts.edu

NMDA-type glutamate receptors (NMDARs) contribute to many forms of long-term potentiation (LTP) and long-term depression (LTD). NMDARs are heteromers containing calcium-permeating neuronal receptor 1 (NR1) subunits and a variety of NR2 subunits. Evidence suggests that, in the CA1 region of the hippocampus, NR2A-containing NMDARs promote LTP whereas NR2B-containing receptors promote LTD. However, the calcium sensors that distinguish between these signals to promote the appropriate form of synaptic plasticity are not known. Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 are highly similar calcium-stimulated exchange factors that activate Ras and Rac GTPases. Here, using a set of Ras-GRF knock-out mice, we show that Ras-GRF2 contributes predominantly to the induction of NMDAR-dependent LTP, whereas Ras-GRF1 contributes predominantly to the induction of NMDAR-dependent LTD in the CA1 region of the hippocampus of postpubescent mice (postnatal days 25–36). In contrast, neither Ras-GRF protein influences synaptic plasticity in prepubescent mice (postnatal days 14–18). Ras-GRF2 mediates signaling from (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid-sensitive (NVP-AAM077-sensitive) (NR2A-containing) NMDARs to the Ras effector extracellular signal-related protein kinase 1/2 (Erk1/2) mitogen-activated protein (MAP) kinase, a promoter of NMDAR-induced LTP at this site. In contrast, Ras-GRF1 mediates signaling from ifenprodil-sensitive (NR2B-containing) NMDARs to the Rac effector p38 MAP kinase, a promoter of LTD. These findings show that, despite their similar functional domain organization, Ras-GRF1 and Ras-GRF2 mediate opposing forms of synaptic plasticity by coupling different classes of NMDARs to distinct MAP kinase pathways. Moreover, the postnatal appearance of Ras-GRF-dependent LTP and LTD coincides with the emergence of hippocampal-dependent behavior, implying that Ras-GRF proteins contribute to forms of synaptic plasticity that are required specifically for mature hippocampal function.

Key words: Ras-GRF1; Ras-GRF2; LTP; LTD; synaptic plasticity; Ras; NMDA receptors

---

Received Sept. 20, 2005; revised Dec. 23, 2005; accepted Dec. 29, 2005.

Correspondence should be addressed to Larry A. Feig, Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. Email: larry.feig{at}tufts.edu

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