Abstract
RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.
Highlights
The ability to distinguish similar experiences is a critical aspect of memory
RAS-GRF1 Begins to Contribute to HFS-induced long term potentiation (LTP) at 2 Months of Age in the CA1, but Not CA3 or Dentate Gyrus, Regions of the Hippocampus—Using Ras-Grf knock-out mice, we previously showed that RAS-GRF1 is predominantly involved in mediating NMDA-type glutamate receptor (NMDAR) activation of LTD, whereas RAS-GRF2 is predominantly involved in mediating NMDAR activation of LTP at the CA3/CA1 synapse beginning at approximately day 30 in mice [5]
LTP generated by TBS (15 bursts of four pulses at 100 Hz delivered at an interburst interval of 200 ms) was normal in 2-month-old RAS-GRF1 knock-out mice (Fig. 1B) (WT, 159.43 Ϯ 2.77% (n ϭ 8 slices from five mice) versus 157.80 Ϯ 1.69% (n ϭ 9 slices from five grf1Ϫ/Ϫ mice; p Ͼ 0.05)) as we showed previously for 1-month-old mice [5]. 2-Monthold Ras-Grf2 knock-out mice show the opposite results, normal HFS LTP but defective TBS LTP
Summary
Results: Contextual discrimination involves LTP promoted by calcium-permeable AMPA-type glutamate receptors, RAS-GRF1 and p38 MAP kinase. We show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). One class of signaling molecules that have been implicated in synaptic plasticity consists of the RAS-GRF1 and RAS-GRF2 guanine nucleotide exchange factors [4] These proteins have the capacity to activate RAS and RAC GTPases through their CDC25 and DH domains, respectively. We demonstrate that p38 MAP kinase activation is involved in an age-dependent LTP mechanism, mediated by calcium-permeable AMPA receptors and RASGRF1, that contributes to the acquisition at ϳ2 months of age of the ability of mice to distinguish closely related contexts
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