Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor - PubMed (original) (raw)
Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor
B A Bahr et al. J Neurosci. 1997.
Abstract
Peptides known to block the extracellular interactions of adhesion receptors belonging to a subclass of the integrin family were tested for their effects on the stabilization of long-term potentiation (LTP) in hippocampal slices. Theta burst stimulation delivered after infusions of Gly-Ala-Val-Ser-Thr-Ala (GAVSTA) resulted in a potentiation effect that decayed steadily over a period of 40 min; LTP elicited in the presence of inactive control peptides remained stable over this time period. GAVSTA had no detectible influence on baseline responses, induction processes, or the initial degree of potentiation. Infusions of integrin antagonists after application of theta bursts also resulted in the occurrence of a decremental form of LTP. Affinity chromatography was then used in an effort to identify targets of the structurally dissimilar integrin blockers that disrupt LTP stabilization. Both integrin antagonists Gly-Arg-Gly-Asp-Ser-Pro and GAVSTA eluted a major species of 55 kDa (synaptegrin-1) from GRGDSP-affinity columns that had been loaded with solubilized synaptic membranes; lesser concentrations of three polypeptides of approximately 20, 27, and 30 kDa were also collected. Synaptegrin-1 was labeled by antibodies to the RGDS-binding integrin alpha5beta1. In addition, the synaptegrin, as well as the 27 kDa, protein was found to copurify with pre- and postsynaptic markers during the isolation of forebrain synaptosomes. These results indicate that a matrix recognition event occurring several minutes after induction of LTP is a necessary step in the stabilization of potentiated synapses; they also identify an integrin-like matrix receptor of 55 kDa that may contribute to this event.
Figures
Fig. 1.
Effects of the integrin blocking peptide GAVSTA on LTP. a_–_c, Field EPSPs evoked by single stimulation pulses delivered to the Schaffer commissural projections were recorded in CA1 dendrites of hippocampal slices. Responses recorded at 2 (a) and 40 min (b,c) after TBS are shown superimposed with baseline EPSPs recorded before TBS in slices preincubated with 1 m
m
GAVSTA (a, b) or 2 m
m
control peptide ASG (c) for 50–90 min (calibration: 1 mV, 10 msec). d, The time course of potentiation in the presence of 0.8 m
m
GAVSTA (n = 16) or control peptide (2 m
m
ASG or 0.8 m
m
GRADSP;n = 16 total) is shown with the results expressed as the percent change (group mean ± SEM) from the average baseline field EPSP slope, measured during 15 min of recording before TBS (arrow). Open circles represent responses in GAVSTA-treated slices (n = 10) before administration of TBS.
Fig. 2.
GAVSTA does not affect baseline synaptic transmission in nonpotentiated pathways. Four hippocampal slices were preincubated with 1 m
m
GAVSTA for 50–60 min. Subsequently, basal synaptic responses (open circles) were simultaneously recorded in one pathway while TBS was applied to the second pathway (solid circles) at time 0 (arrow). Results are expressed as the percent change from the average baseline field EPSP slope (group mean ± SEM).
Fig. 3.
GAVSTA does not affect the postsynaptic responses to bursts of afferent stimulation used in the TBS induction paradigm of LTP. a, b, The initial burst response of a series of 10 is superimposed with the second facilitated response measured in slices preincubated with 2 m
m
ASG (a) or 0.8 m
m
GAVSTA (b) for 50–90 min (calibration: 1 mV, 20 msec). c, The histogram shows the percent increase in burst area (mean ± SEM) across the train of responses, as compared with the initial burst response, in control (2 m
m
ASG or 0.8 m
m
GRADSP; n = 14) and GAVSTA (0.8 m
m
;n = 14) slices.
Fig. 4.
GAVSTA does not affect the NMDA receptor-mediated EPSP component. Responses elicited by single stimulation pulses delivered to the Schaffer commissural projections were recorded in the presence of 20 μ
m
CNQX and low Mg2+ (50–100 μ
m
). The plotted data are group means (± SEM) represented as the percent change from the average baseline slope measured 15 min before the start of constant infusion of 1 m
m
GAVSTA (n = 7). Subsequent infusion of the NMDA receptor antagonist AP5 (200 μ
m
) was initiated where indicated. Typical responses recorded at the times indicated above the graph are shown.
Fig. 5.
Effect of an integrin antagonist applied immediately after the induction of LTP. A summarizes results (mean ± SEM) for a group of control (n = 7) and GRGDSP-treated (n = 10) slices, whereas B illustrates individual experiments. Infusion of GRGDSP (0.5 m
m
; see_bar_) was begun within 1 min of the conclusion of a train of 10 theta bursts (TBS) applied to the Schaffer commissural fibers. C shows an example in which baseline responses were simultaneously recorded from a second pathway while TBS was delivered to another. Baseline EPSPs recorded before and after 30 min of GRGDSP infusion (traces 1, 2) are shown, as are potentiated responses measured 2 min (trace 3) and 80 min (trace 4) after TBS (trace 1 is the nondotted record).
Fig. 6.
Basal synaptic transmission is unaffected by GRGDSP. Field EPSPs were elicited by single stimulation pulses delivered to the Schaffer commissurals of four slices, and the initial slope was measured. The plotted data are group means (± SD) represented as the percent of the initial baseline established over an 18 min period before a 55 min infusion of GRGDSP (0.5 m
m
). Responses were continually recorded during washout of the peptide.
Fig. 7.
Effect of RGDS peptides on previously established LTP. Field EPSPs were recorded in CA1, and LTP was induced at time 0 with TBS (arrow). RGDS (1 m
m
RGDS or 0.2 m
m
GRGDSP; n = 13 total) or control (vehicle or 6 m
m
tetraglycine; n = 17 total) peptides were infused into the interface chamber 10 min after TBS was administered to a slice (bar). Group means (± SEM) of the change in baseline EPSP initial slope (circles) are shown. Two-tailed t test between the two groups of slices at 70 min after induction:p < 0.01.
Fig. 8.
Affinity purification of RGDS-binding proteins. Solubilized SPMs isolated from whole brain (A1_-3) and hippocampus (B1_-3) were applied to separate columns containing immobilized GRGDSPK, as described in Materials and Methods. Silver-stained electrophoresis samples consisted of concentrated fraction aliquots collected from column volumes containing nonbound material (A1), the fifth wash (A2), and GRGDSP eluant (A3). The column loaded with hippocampal SPMs was washed thoroughly, and fractions were collected containing GAVSTA eluant (B1), the wash after the GAVSTA elution (B2), and the subsequent GRGDSP eluant (B3). Lane 4 contains 50 μg cortical SPM protein and was immunoblotted with anti-β1antibodies. The electrophoretic positions of molecular weight standards (in kilodaltons) are shown on the left for lanes_A1–3 and on the right for lanes_B1–4. Arrows, 55 kDa synaptegrin-1;arrowheads, 20, 27, and 30 kDa RGDS-binding proteins (see text).
Fig. 9.
Comigration of RGDS-binding proteins and synaptic markers across density gradients. Fresh forebrain P2 suspensions were applied to 3–25% Percoll gradients to isolate synaptosomes, as described in Materials and Methods. The interfacial zones of the gradients were separated, washed by centrifugation, and hyposmotically treated. Aliquots of the soluble fraction from interfacial zones 2–5 were concentrated and prepared for immunoblotting (lanes 1–4, respectively); lysed membranes from zones 1–5 (lanes 5–9; 70 μg protein each) were also immunoblotted. The following antibodies were used: anti-β1 (labeled 55 kDa synaptegrin-1), anti-αvβ3 (labeled a 27 kDa antigen), anti-GluR1, anti-GluR2/3, and anti-synaptophysin.
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