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Comparative Study
. 2006 Oct 18;26(42):10888-109898.
doi: 10.1523/JNEUROSCI.0878-06.2006.

Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm

Oleg Senkov  1 , Mu Sun, Birgit Weinhold, Rita Gerardy-Schahn, Melitta Schachner, Alexander Dityatev
Affiliations
Comparative Study

Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm

Oleg Senkov et al. J Neurosci. .

Abstract

Polysialic acid (PSA) regulates functions of the neural cell adhesion molecule (NCAM) during development and in neuroplasticity in the adult; the underlying mechanisms at different phases of learning and memory consolidation are, however, unknown. To investigate the contributions of PSA versus the extracellular domain of the NCAM glycoprotein backbone to synaptic plasticity, we applied NCAM, PSA-NCAM, and PSA to acute slices of the hippocampal CA1 region of NCAM-deficient mice and measured their effects on long-term potentiation (LTP). Remarkably, only PSA and PSA-NCAM, but not NCAM restored normal LTP. Application of these molecules to the dorsal hippocampus of wild-type mice showed that PSA-NCAM and PSA, but not NCAM, injected before fear conditioning, impaired formation of hippocampus-dependent contextual memory. Consolidation of contextual memory was affected by PSA-NCAM only when injected during its late, but not early phases. None of the tested compounds disturbed extrahippocampal-cued memory. Mice lacking the polysialyltransferase (ST8SialV/PST) responsible for attachment of PSA to NCAM in adulthood showed a mild deficit only in hippocampal contextual learning, when compared with NCAM-deficient mice that were disturbed in both contextual and cued memories. Contextual and tone memory in NCAM-deficient mice could be partially restored by injection of PSA-NCAM, but not of NCAM, into the hippocampus, suggesting that the impact of PSA-NCAM in synaptic plasticity and learning is not mediated by modulation of NCAM-NCAM homophilic interactions. In conclusion, our data support the view that polysialylated NCAM is involved in both formation and late consolidation of contextual memory.

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Figures

Figure 1.
Figure 1.
In vitro LTP recording from the CA1 hippocampal region of NCAM deficient (NCAM−/−) and wild-type (NCAM+/+) mice. A, Injection of PSA-NCAM-Fc (100 μg/ml) into slice from NCAM−/− mice before first theta-bust stimulation (TBS-1) significantly increased LTP at the recording site adjacent to the injection site as compared with LTP recorded at the control site in the same slice. LTP induced by a second theta-bust stimulation (TBS-2) after PSA-NCAM-Fc injection was also higher at the injected than at the control site. B, Injection of NCAM-Fc (100 μg/ml) failed to rescue LTP induced by either TBS-1 or TBS-2 in NCAM−/− mice. C, Injection of PSA (100 μg/ml) restored LTP in NCAM−/− mice. D, Injection of PSA (100 μg/ml) impaired LTP in NCAM+/+ mice. E, PSA injected at a concentration of 300 μg/ml did not rescue LTP in NCAM−/− mice. F, Injection of PSA (100 μg/ml) starting 10 min after TBS-2 rather than 20 min before TBS-1 as in A–E did not affect LTP in NCAM−/− mice. All data are represented as mean slope + SEM of fEPSPs normalized to the baseline values. *p ≤ 0.05 (paired t test). Time intervals of injection are indicated by horizontal bars.
Figure 2.
Figure 2.
Effects of pretraining injection of compounds on fear conditioning. A, Scheme showing manipulations performed in this series of experiments. Compounds were injected 4 h before training. A 100 s trial (B) was used to evaluate the baseline response to the conditioned context (CC+) before training. B, Pretraining injection of PSA-NCAM-Fc or PSA, but not NCAM-Fc, impaired contextual memory when tested on the first (both compounds) and third (PSA-NCAM-Fc only) days after training (trials 1 and 3, respectively). Mice injected with the Fc-fragment (Fc) and chondroitin sulfate (CHS) served as controls. Fc- and chondroitin sulfate-injected mice did not differ in contextual memory from unoperated (UO) and ACSF-injected mice, respectively. Fear memory was measured as the percentage of time that mice spent in the freezing state. Analysis of freezing during baseline trial B showed no difference between injected groups. C, Pretraining injection of tested compounds did not affect freezing time in response to paired (CS+) and unpaired (CS−) tones during trials 2 and 3. Discrimination between CS+ and CS− tones was also not different between injected groups. #p ≤ 0.05, ####p ≤ 0.001 (the effect of treatment by two-way ANOVA); *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.001 (post hoc FLSD test, as compared with corresponding controls, Fc or chondroitin sulfate, for corresponding days); +p < 0.05, ++p < 0.01, +++p < 0.005, ++++p < 0.001 (Wilcoxon test).
Figure 3.
Figure 3.
Effects of post-training injection of compounds during early consolidation phase of fear conditioning. A, Scheme showing manipulations performed in this series of experiments. A 100 s trial (B) was used to evaluate the baseline response to the conditioned context (CC+) before training. Compounds were injected 2 h after initiation of training. B, None of the mice showed any impairment in contextual memory when tested on the first and third days after training (trials 1 and 3, respectively) and during trial B. Mice injected with the Fc-fragment (Fc) and chondroitin sulfate (CHS) served as controls. C, Post-training injection of tested compounds did not affect cued memory during trials 2 and 3. Discrimination of paired (CS+) versus unpaired (CS−) tones also did not differ between groups. +p < 0.05 (Wilcoxon test).
Figure 4.
Figure 4.
Effects of post-training injections of compounds during late consolidation phase of fear conditioning. A, Scheme showing manipulations performed in this series of experiments. A 100 s trial (B) was used to evaluate the baseline response to the conditioned context (CC+) before training. Compounds were injected 6 h after initiation of training. B, Among injected compounds, only PSA-NCAM-Fc impaired contextual memory tested in CC+ on the first and third days after training (trials 1 and 3, respectively). Mice injected with the Fc-fragment (Fc) and chondroitin sulfate (CHS) served as controls. There was no difference between injected groups during trial B. C, Post-training injection of compounds did not affect cued memory and discrimination between paired (CS+) versus unpaired (CS−) tones. ##p ≤ 0.01 (ANOVA); **p ≤ 0.01 (post hoc FLSD test as compared with Fc for day 1); +p < 0.05 (Wilcoxon test).
Figure 5.
Figure 5.
Fear conditioning of PST-deficient mice (PST−/−) and corresponding wild-type controls (PST+/+). A, PST−/− mice showed significantly less freezing in the conditioned context (CC+) compared with PST+/+ mice. A 100 s trial (B) was used to evaluate the baseline response to the conditioned context (CC+) before training. There was no difference between groups during trial B. B, Cued memory was normal on the second and third days after fear conditioning (trials 2 and 3) in PST−/− mice. Discrimination of paired (CS+) versus unpaired (CS−) tones also did not differ between genotypes. ###p ≤ 0.005 (ANOVA); *p ≤ 0.05, ***p ≤ 0.005 (post hoc FLSD test; as compared with PST+/+ for corresponding days); +p < 0.05 (Wilcoxon test).
Figure 6.
Figure 6.
Effects of pretraining injection of compounds on fear conditioning in NCAM deficient (NCAM−/−) mice. A, Scheme showing manipulations performed in this series of experiments. Compounds were injected 4 h before training. A 100 s trial (B) was used to evaluate the baseline response to the conditioned context (CC+) before training. B, NCAM−/− mice showed robust impairment of contextual memory tested on the first and third days after training (trials 1 and 3, respectively) compared with their wild-type littermates, NCAM+/+. The deficit in contextual memory in NCAM−/− mice was partially rescued by pretraining injection of PSA-NCAM-Fc, but not by NCAM-Fc, as compared with Fc. Injections of PSA-NCAM-Fc into NCAM+/+ mice impaired contextual memory. All mice showed similar freezing responses during the baseline period (trial B). C, NCAM−/− mice were impaired in cued memory compared with NCAM+/+ mice. This deficit in NCAM−/− mice could be rescued by the pretraining injection of PSA-NCAM-Fc but not NCAM-Fc. Other groups showed no effect of treatment in cued memory processing as well as in discrimination of CS+ and CS− tones, as compared with Fc injected mice. #p ≤ 0.05, ##p ≤ 0.01, ###p ≤ 0.005, ####p ≤ 0.001 (ANOVA); *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.005, ****p ≤ 0.001 (post hoc FLSD for comparisons indicated for ANOVA, for corresponding days); +p < 0.05, ++p < 0.01, +++p < 0.005, ++++p < 0.001 (Wilcoxon test).
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