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. 1998 May 1;18(9):3460-9.
doi: 10.1523/JNEUROSCI.18-09-03460.1998.

Time-dependent reversal of long-term potentiation by an integrin antagonist

U Stäubli  1 , D Chun, G Lynch
Affiliations

Time-dependent reversal of long-term potentiation by an integrin antagonist

U Stäubli et al. J Neurosci. .

Abstract

The integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) was applied by local ejection to one of two recording sites in hippocampal slices at various times before and after long-term potentiation (LTP) was induced at both sites with theta burst stimulation. Applications 10 min before, immediately after, and 10 min after induction caused LTP at the experimental site to decay steadily relative to that at the within-slice control site. However, application at 25 min or more after induction had no detectable effect on potentiation. Similar results were obtained when the integrin antagonist was perfused into the slice rather than applied locally. The time period after induction during which GRGDSP interfered with LTP consolidation corresponds to that during which LTP is susceptible to reversal by low-frequency afferent stimulation and newly formed memories are vulnerable to various disruptive treatments. Comparable experiments using a peptide that blocks an extracellular binding site of neural cell adhesion molecules (NCAMs) did not yield time-dependent reversal of LTP; i.e., an antagonist that interacts with the fourth immunoglobulin-like domain reduced LTP when applied before induction but not afterward. Moreover, LTP formation occurred normally in the presence of an antibody against the fibronectin repeat domain of NCAM. These results suggest that integrin activation and signaling occurring over several minutes after LTP induction are necessary for stabilizing synaptic potentiation and by inference may be required for the conversion of new memories into a not readily disrupted state.

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Figures

Fig. 1.
Fig. 1.
Time-dependent reversal of LTP by integrin antagonist GRGDSP. A–E, Experiments in which LTP in area CA1 was simultaneously monitored at a test (•) and control site (○) within the same slice. Local ejection of the integrin antagonist GRGDSP (0.5 mm) at the test site was initiated at various times before and after LTP induction, i.e., 10 min before (A) (n = 6), immediately after (B) (n = 4), 10 min after (C) (n = 5), 25 min after (D) (n = 6), and 45 min after TBS (E) (n = 4). Each data point represents the group mean of one response per animal (±SEM). A′, Superimposed representative responses from an individual experiment. The potentials were recorded from the control and within-slice test site at the times indicated by the numbers inA, i.e., 10–15 min before as well as 5 min and 45 min after TBS, with the dotted waveform representing the response recorded at 45 min. C′, E′, Same as inA′, except that the responses are taken from experiments included in the groups summarized in C andE. Calibration: 1 mV, 10 msec.
Fig. 2.
Fig. 2.
GRGDSP, but not the control peptide GRADSP, interferes with LTP stabilization. A, Same experiments as those illustrated in Figure 1, except that the data (mean ± SEM) for all groups are united in one graph and expressed as the ratio of the percent LTP at the test site divided by the percent LTP recorded simultaneously at the within-slice control site (□: start of infusion 10 min before TBS, n = 6; •: immediately after TBS, n = 4; ▵: 10 min after TBS,n = 5; ▴: >25 min after TBS,n = 10). B, GRGDSP was applied at a higher concentration (2 mm) and earlier, i.e., 20 min before LTP induction at both test and control site in a group of seven slices. C, Control experiments examining the effect of the non-RGD-containing peptide GRADSP (0.5 mm) in a group of seven slices, using the same experimental protocol as inB.
Fig. 3.
Fig. 3.
Whole-slice perfusion of integrin antagonist GRGDSP causes time-dependent reversal of LTP. A–D, Bath perfusion of the peptide (0.5 mm) was initiated at different times (horizontal bar) before and after LTP induction: A, 10 min before TBS (n = 5); B, immediately after TBS (n = 4); C, 10 min after TBS (n = 6); andD, 30 min (n = 5) and 45 min (n = 4) after TBS (data pooled for both time points). Each circle represents the group mean of one response per animal (±SEM).
Fig. 4.
Fig. 4.
MS2, an NCAM antagonist, reduces the amount of initial LTP when applied before, but not after, induction.A–C, Experiments in which LTP was induced simultaneously at control (○) and test (•) sites within the same slice. The polypeptide MS2, which binds to the fourth immunoglobulin domain of NCAM, was pressure-ejected at 2 μg/μl at the test site, starting at various times (horizontal bar) before and after LTP induction: A, 10 min before (n = 10); B, immediately after (n = 7); or C, 10 min after TBS (n = 4). Each data point represents the group mean of one response per animal (±SEM). Superimposed waveforms on the right of each graph illustrate representative recordings from individual experiments taken at the times indicated by the numbers in the graphs.Dotted waveform is the response collected 45 min after TBS (A, B) or start of peptide application (C). Calibration: 1 mV, 10 msec.
Fig. 5.
Fig. 5.
NCAM antibody does not affect LTP induction, development, or stabilization. A, An antibody against the fibronectin type III repeat domain of NCAM was pressure-ejected at 4 μg/μl, starting 10 min (n = 4) and 20 min (n = 5) before LTP induction (data pooled for both time points). B, Same as in A, except that antibody application was initiated 30 min before LTP induction (n = 5). C, Representative waveforms from an individual experiment taken at the times indicated by thenumbers in A. Calibration: 1 mV, 10 msec.
Fig. 6.
Fig. 6.
MS2 reduces facilitation of postsynaptic theta burst responses during LTP-inducing afferent stimulation, whereas GRGDSP, GRADSP, and the NCAM antibody have no effect. A, Increase in burst area (mean ± SEM) across a train of 10 bursts expressed relative to the initial burst response for both control (n = 5) and test (n = 5) pathways of slices in which GRGDSP (2 mm) was applied locally at the test site starting 20 min before LTP induction.B, Same as in A, but showing comparisons between control (n = 5) and test (n = 7) pathways of slices involving local ejection of MS2 (2 μg/μl) at the test site starting 20 min before TBS.C, Data adapted from A andB, comparing results between the two groups of test pathways. D, Comparisons of the amount of burst facilitation between test pathways of slices exposed to the control peptide GRADSP (n = 8) or MS2 (n = 7), with drug application beginning 20 min before TBS in both cases. E, Comparisons of burst facilitation between test pathways of slices in which GRGDSP (2 mm; n = 5) or NCAM antibodies (4 μg/μl; n = 5) were applied locally, starting 20 min before TBS. F, Data adapted from Cand E showing comparisons between test pathways treated with MS2 (n = 7) or NCAM antibody (n = 5). Significance levels: *p < 0.05, **p < 0.01;t test.
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