Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene - PubMed (original) (raw)

Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene

C W Xie et al. Proc Natl Acad Sci U S A. 2000.

Abstract

We examined the learning and memory of neurotrophin-4 (NT4)-/- mice by using fear conditioning. In both cue and context conditioning, we found significant deficits in the NT4 mutants at 2 and 24 h after training but not at 30 min. Hippocampal slices from the mutant mice showed normal basal synaptic transmission, short-term plasticity, and decremental long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses. These findings, together with the normal short-term memory, suggest that the hippocampal development of NT4-/- mice is largely unaffected. However, consistent with the long-term memory defects, the long-lasting LTP at the same synapses was attenuated significantly in the mutant mice. Our results suggest that NT4 plays a physiological role essential for hippocampus- and amygdala-dependent long-term memory and hippocampal long-lasting LTP and that NT4 may be useful in the therapy of acquired disorders of learning and memory.

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Figures

Figure 1

Figure 1

Contextual conditioning with a single training trial. (A) The freezing of one group of NT4−/− (n = 8) and wt (n = 8) mice during training. The solid line indicates the duration of the tone (CS). The arrow indicates the 2-s foot shock. ANOVA showed no significant difference between NT4−/− and wt mice (P = 0.31). The freezing responses of all other groups of mice for both context and cue conditioning tests are very similar to what is shown in A. (B–D) Three separate groups of NT4−/− and wt mice were tested for contextual conditioning at 30 min (B), 2 h (C), and 24 h (D) after training. ANOVA showed highly statistically significant differences between NT4−/− and wt mice at 2 and 24 h (P < 0.0001) but no significant difference at 30 min (P = 0.12).

Figure 2

Figure 2

Cue conditioning with a single training trial. (A–C) Three groups of NT4−/− and wt mice were tested for cued conditioning at 30 min (A), 2 h (B), and 24 h (C) after training. Similar to contextual conditioning, ANOVA showed statistically significant differences between NT4−/− and wt mice at 2 h (P = 0.027) and 24 h (P = 0.004) but no significant difference at 30 min (P = 0.42).

Figure 3

Figure 3

Sensitivity to foot shock in NT4−/− and wt type mice. The sensitivity to foot shock was determined by assessing the amount of current required to elicit three stereotypical responses in NT4−/− and wt mice. Eight mice of each genotype were tested, and there was no difference between NT4−/− and wt type mice (P > 0.25). The level of current required to cause vocal responses from NT4−/− mice was lower than that of wt mice but did not reach statistical significance (P = 0.051).

Figure 4

Figure 4

Basal synaptic transmission and PPF are normal in area CA1 of hippocampal slices from NT4−/− mice. (A) The scatter plot of fEPSP slopes vs. fiber volley amplitudes during Schaffer collateral stimulation. No marked difference was shown in the distribution of values obtained from mutants (n = 13 slices; eight mice) and wt mice (n = 9 slices; eight mice). (B) PPF was calculated as percentage of increase of the second fEPSP slope from the first one. No significant difference was detected between the mutants and wt mice for the facilitation measured at indicated interpulse intervals (n = 9 slices; six mice for each group; P > 0.30 for all comparisons).

Figure 5

Figure 5

NT4 mutation attenuates the L-LTP but not D-LTP in area CA1. (A) D-LTP induced by single high-frequency stimulation (HFS; 100 Hz; 1 s). No significant difference was observed between the wt (n = 12 slices; 10 mice) and mutant mice (n = 11 slices; 8 mice) at all time points tested. (B) L-LTP induced by four stimulus trains (100 Hz; 1 s) at 5-min intervals. Note the wt mice (n = 8 slices; six mice) showed robust and lasting LTP over a period of 3 h. In contrast, the mutant mice (n = 7 slices; seven mice) displayed a continuously decaying potentiation after receiving the same tetanization (P < 0.05 for all time points tested). (Insets) Sample fEPSP traces recorded from area CA1 of wt and mutant slices before and 3 h after four stimulus trains. (Bars = 2 mV and 10 ms.)

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