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.
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.
Li
Shaomin
S
Department of Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Tian
Xuejun
X
Hartley
Dean M
DM
Feig
Larry A
LA
D000818:Animals; D019706:Excitatory Postsynaptic Potentials; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D020666:ras-GRF1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D020735:Guanine Nucleotide-Releasing Factor 2; D016194:Receptors, N-Methyl-D-Aspartate; D020666:ras-GRF1