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University of Texas, Department of Biology and the Cajal Neuroscience Research Center, San Antonio, Texas 78249)
Theta-burst stimulation (TBS) induces Schaffer collateral-CA1 synaptic long-term potentiation (LTP; 1,2), an experimental model of synaptic plasticity believed to reflect physiological processes during normal learning and memory. Various adhesion receptors may play a role in LTP (3), including integrins, transmembrane signaling receptors that link extracellular ligands to the actin cytoskeleton (4). A principal recognition signal for some integrins is the tripeptide Arg-Gly-Asp (RGD), a sequence found in various extracellular matrix and cell-surface proteins. Indeed, integrin-binding to endogenous ligand is perturbed by the peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) (5). To assess the role of integrins in LTP, the effect of GRGDSP was tested on the CA1 field excitatory post-synaptic potential (fEPSP) of the rat hippocampus. In previous studies, we found that 250 µM GRGDSP, half the concentration reported by others (1), was sufficient to significantly reduce LTP (2), even when applied for 15 min during a period that included 10 min pre- to 5 min post-TBS (unpubl. data). Also, application of 250 µM GRGDSP at 5 or 30 min post-TBS had no effect on CA1 LTP. These results raised questions about the time frame of integrin binding during the process of LTP induction and expression. Current experiments, summarized in graph form in Figure 1, now suggest that a critical period of integrin-binding activity necessary for LTP occurs within the first few minutes following TBS.
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When 250 µM GRGDSP was applied—beginning 10 min pre-TBS and concluded at 5 min post-TBS (see Fig. 1A, solid bar; 7.0 ± 3.8%, n = 3)—the percent change from baseline of the fEPSP slope, measured at 60 min post-TBS, was substantially reduced when compared with artificial cerebral spinal fluid (aCSF) controls (Fig. 1A, open bar; 37.8 ± 16.0%, n = 3). These experiments replicate previous studies (2) and confirm peptide activity. However, a 10-min application of 250 µM GRGDSP, with a 30–60 s wash-out immediately before TBS, did not reduce LTP (see Fig. 1B, solid bar; 48.3 ± 17.9%, n = 3), as compared with aCSF (Fig. 1B, open bar; 28.2 ± 13.2%, n = 6), or 250 µM of the inactive peptide, GRADSP (Fig. 1B, shaded bar; 43.3 ± 20.9%, n = 3; ANOVA, P > .05). Finally, to determine whether a decrease in LTP by post-TBS application of GRGDSP may be concentration-dependent within ranges previously tested (1,2), a 40-min bath application of 500 µM GRGDSP, beginning 5 min post-TBS, was tested. This concentration also did not decrease CA1 LTP (Fig. 1C, solid bar; 84.7 ± 30.9%, n = 3) when compared with aCSF controls (Fig. 1C, open bar; 58.0 ± 14.3%, n = 7; t test, P > .05).
Based on these new data, we conclude that GRGDSP disrupts LTP within the first few minutes after TBS, and hypothesize that tetanic stimulation may initiate a process that modifies the availability of integrin to bind ligand. The integrin-binding peptide, GRGDSP, is thought to decrease LTP by competing for integrin binding sites in the extracellular matrix that recognize the RGD motif; successful binding by the peptide then disrupts normal integrin function during LTP expression and maintenance. The data presented here, however, suggest that integrins may not be available to bind GRGDSP before TBS, but are quickly and briefly available after TBS.
Supported by a Specialized Neuroscience Research Projects grant (NINDS NS39409; RGL/JLM) and the Ewing Halsell Foundation (JLM).
Literature Cited
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  P. Gui, X. Wu, S. Ling, S. C. Stotz, R. J. Winkfein, E. Wilson, G. E. Davis, A. P. Braun, G. W. Zamponi, and M. J. Davis Integrin Receptor Activation Triggers Converging Regulation of Cav1.2 Calcium Channels by c-Src and Protein Kinase A Pathways J. Biol. Chem., May 19, 2006; 281(20): 14015 - 14025. [Abstract] [Full Text] [PDF]
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E. A. Kramar, J. A. Bernard, C. M. Gall, and G. Lynch Integrins Modulate Fast Excitatory Transmission at Hippocampal Synapses J. Biol. Chem., March 14, 2003; 278(12): 10722 - 10730. [Abstract] [Full Text] [PDF]
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