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. 2003 Aug 6;23(18):7107-16.
doi: 10.1523/JNEUROSCI.23-18-07107.2003.

Integrin requirement for hippocampal synaptic plasticity and spatial memory

Chi-Shing Chan  1 , Edwin J Weeber, Sindhu Kurup, J David Sweatt, Ronald L Davis
Affiliations

Integrin requirement for hippocampal synaptic plasticity and spatial memory

Chi-Shing Chan et al. J Neurosci. .

Abstract

The establishment of memory requires coordinated signaling between presynaptic and postsynaptic terminals in the CNS. The integrins make up a large family of cell adhesion receptors that are known to mediate bidirectional signaling between cells or between cells and their external environment. We show here that many different integrins, including alpha3 and alpha5, are expressed broadly in the adult mouse brain and are associated with synapses. Mice with genetically reduced expression of alpha3 integrin fail to maintain long-term potentiation (LTP) generated in hippocampal CA1 neurons. Mice with reduced expression of the alpha3 and alpha5 integrins exhibit a defect in paired-pulse facilitation. Mice with reduced expression of alpha3, alpha5, and alpha8 are defective in hippocampal LTP and spatial memory in the water maze but have normal fear conditioning. These results demonstrate that several different integrins are involved in physiological plasticity and provide the first evidence of their requirement for behavioral plasticity in vertebrates.

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Figures

Figure 3.
Figure 3.
Effects of integrin deficiency on hippocampal LTP in area CA1. LTP was induced by using 100 Hz stimulation (arrow). Data points were normalized to the average response during an initial 20 min pretetanus stimulation period. A, B, Similar deficits in LTP were observed at 60 min post-tetanus in mice heterozygous for integrin α3 knock-out in either C57/Bl6 (n = 7; WT, n = 14) or 129/SvEv (n = 7; WT, n = 7) backgrounds. C-E, Normal LTP was recorded in α5/+ (n = 9; WT, n = 9), α8/+ (n = 11; WT, n = 8), and α5/+;α8/+ (n = 9; WT, n = 9) heterozygotes. F-H, LTP immediately after HFS was normal in α3/+;α5/+ (n = 9; WT, n = 14) heterozygotes but was reduced in α3/+;α8/+ (n = 8; WT, n = 8) and α3/+;α5/+;α8/+ heterozygotes (n = 5; WT, n = 9). LTP measured at 60 min after HFS was deficient in all three genotypes. No LTP was present in the triple heterozygote. Significant differences in pEPSP were found between the mutant and WT animals at t = 60 min in A, B and F-H.
Figure 1.
Figure 1.
Analysis of integrinα3 expression in the adult brain. A, Expression in various regions of the brain as assayed by RT-PCR. Cx, Cortex; Hp, hippocampus; Cb, cerebellum; Th, thalamus; OB, olfactory bulb. B-E, Immunohistochemistry of the cortex (B), hippocampus (C, D), and cerebellum (E) with the use of an anti-α3 integrin antibody. Cellular staining was detected in all six layers of the cortex (I-VI), in the granule cells of the dentate gyrus (DG), in the pyramidal cells of the CA1 and CA3 regions, and in Purkinje neurons. At higher magnification (40 × objective), staining of the processes of the pyramidal cells (D) and Purkinje neurons (E) was also detectable (arrows).
Figure 2.
Figure 2.
Synaptosome localization of α3 and α5 integrins in cortex and hippocampus. A, Immunoblot of integrin α3 protein in total forebrain extracts of α3 integrin heterozygous (α3/+) adults and in wild-type (+/+) and homozygous (α3/α3) mutant fetuses. The full-length α3 integrin subunit is identified; the asterisk identifies a larger integrin that is specific to the adult. Synaptosomes are shown from the following: lane 1, an α3/α3 homozygous fetus; lanes 2, 4, two individual wild-type fetuses; lanes 3, 5, two individual α3/+ heterozygous adults. B, β1 integrin is coimmunoprecipitated by anti-α3 and anti-α5 antibodies. Lane 1, Immunoblot of β1 integrin protein in total synaptosomal extract; lanes 2-9, proteins from total synaptosomal extract were immunoprecipitated with no antibody (lane 2), preimmune serum for α3-3209 (lane 3), anti-α3 integrin α3-3209 (lane 4), AB1948 (lane 5), AB1920 (lane 6), anti-α5 integrin (lane 7), anti-GluR1 (lane 8), or anti-GluR2 (lane 9) antibodies, followed by immunoblotting with an anti-β1 antibody. C, Immunoblot to compare the level of integrin α3 protein in total forebrain extracts of wild-type and heterozygous integrin adults. Two individual adult animals were used to represent each genotype. The full-length α3 integrin (top) and syntaxin (control; middle) protein are indicated. In the bottom panel the normalized level of α3 protein in each animal was expressed as a percentage relative to the level detected in the first wild-type animal (wt1; see Materials and Methods).
Figure 4.
Figure 4.
Impaired paired-pulse facilitation (PPF) in integrin mutant heterozygotes. PPF was used to assay short-term synaptic plasticity and presynaptic function. Insets, Representative pEPSP traces from PPF experiments with the use of an interpulse interval of 100 msec (mean of 6 successive EPSPs). The first response (dotted line) and second response (solid line) for mutant (a) and wild-type (b) animals are shown. Calibration: 1 mV, 10 msec. Because PPF varies with the size of the first response, the stimulation was adjusted so that the slope of the pEPSP from the first stimulus for all slices was the same. Asterisks indicate a value significantly different from controls (p < 0.05, Student's t test). A-E, PPF was unaffected for the genotypes α3/+ (n = 10; WT, n = 8), α5/+ (n = 7; WT, n = 8), α8/+ (n = 9; WT, n = 13), α5/+; α8/+ (n = 8; WT, n = 9), and α3/+; α8/+ (n = 11; WT, n = 8). F, G, Defective PPF was observed in α3/+; α5/+ (n = 11; WT, n = 10) at interpulse intervals of 75, 100, 150, and 200 msec and in α3/+; α5/+; α8/+ mutants (n = 14; WT, n = 8) at interpulse intervals of 20, 30, 40, 50, 75, 100, and 150 msec.
Figure 5.
Figure 5.
Performance of α3/+;α5/+;α8/+ triple heterozygotes on the water maze task. A, Escape latency during the acquisition phase in the hidden platform task. No significant difference was detected between the mutant heterozygotes (n = 18) and wild-type controls (n = 18) (F(1,27) = 0.72; p = 0.85, ANOVA). B, Percentage of time spent in each quadrant during a probe trial performed 1 hr after the last training trial on day 7. Controls (n = 18) spent significantly more time in the trained quadrant than the triple heterozygotes (n = 18; p < 0.003, Scheffé's post hoc). ANOVA with repeated measures showed further that the controls spent significantly more time in the trained quadrant than in the other quadrants (F(3,68) = 32.53; p < 0.00001), but the triple heterozygotes spent a similar amount of time in all quadrants (F(3,68) = 2.49; p = 0.067). C, Number of platform crossings during the probe trial. Control mice crossed the virtual platform position in the trained quadrant more than the mutants (p < 0.01, Scheffé's post hoc) and crossed this position in the trained quadrant more often than the corresponding position in other quadrants (F(3,68) = 0.32; p = 0.81). D, E, Swim speed and mean escape latency versus trial number during the visible platform task. No significant difference for either measure was detected between control and the triple heterozygotes (F(1,112) = 0.67 and p = 0.697 for swim speed; F(1,112) = 0.35 and p = 0.93 for escape latency). Asterisk indicates a significant difference.
Figure 6.
Figure 6.
Performance of α3/+;α5/+;α8/+ triple heterozygotes in fear-conditioning assays. A, Performance after contextual fear conditioning at 2 and 24 hr after two CS-US pairings. No significant difference in conditioned responding was observed between wild-type (n = 18) and mutant (n = 18) animals at either time point (F(1,34) = 0.405 and p = 0.81 for 2 hr; F(1,34) = 0.54 and p = 0.71 for 24 hr). B, Performance at 24 hr after cued fear conditioning with two CS-US pairings. Both wild-type and triple heterozygous mutants exhibited conditioned responding during the 3 min presentation of the CS (p < 0.000001 for wild-type; p < 0.0003 for the triple heterozygotes). No difference was observed between the two groups either before (p = 0.17) or during (p = 0.42) the presentation of the tone.
Figure 7.
Figure 7.
Normal neuroanatomy in integrin heterozygotes. A-D, Nissl staining of parasagittal sections of sensory cortex (A, B) and hippocampus (C, D) in controls (A, C) and α3/+;α5/+;α8/+ triple heterozygotes (B, D). Layers I-VI in the cortex are indicated. E, F, Immunohistochemical staining of control (E) and α3/+;α5/+;α8/+ (F) hippocampal sections with an anti-syntaxin antibody. DG, Dentate gyrus; CC corpus callosum; Slu, stratum lucidum.
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