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. 2000 Sep 15;20(18):7116-21.
doi: 10.1523/JNEUROSCI.20-18-07116.2000.

Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats

M Mizuno  1 , K Yamada, A Olariu, H Nawa, T Nabeshima
Affiliations

Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats

M Mizuno et al. J Neurosci. .

Abstract

Brain-derived neurotrophic factor (BDNF) regulates both short-term synaptic functions and activity-dependent synaptic plasticity such as long-term potentiation. In the present study, we investigated the role of BDNF in the spatial reference and working memory in a radial arm maze test. The radial arm maze training resulted in a significant increase in the BDNF mRNA expression in the hippocampus, although the expression in the frontal cortex did not change. When spatial learning was inhibited by treatment with 7-nitroindazole, an inhibitor of brain nitric oxide synthase, the increase in the hippocampal BDNF mRNA did not occur. To clarify the causal relation between BDNF mRNA expression and spatial memory formation, we examined the effects of antisense BDNF treatment on spatial learning and memory. A continuous intracerebroventricular infusion of antisense BDNF oligonucleotide resulted in an impairment of spatial learning, although the sense oligonucleotide had no effect. Treatment with antisense, but not sense, BDNF oligonucleotide was associated with a significant reduction of BDNF mRNA and protein levels in the hippocampus. Furthermore, treatment with antisense BDNF oligonucleotide in rats, which had previously acquired spatial memory by an extensive training, impaired both reference and working memory. There were no differences in locomotor activity, food consumption, and body weight between the antisense and sense oligonucleotide-treated rats. These results suggest that BDNF plays an important role not only in the formation, but also in the retention and/or recall, of spatial memory.

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Figures

Fig. 1.
Fig. 1.
Spatial reference (A) and working (B) memory formation in rats treated with vehicle (n = 20) and 7-NI (n = 14). 7-NI (50 mg/kg) was administered p.o. every day 60 min before each training trial. Each value represents the mean ± SE. 7-NI significantly impaired reference (p < 0.001) and working memory (p < 0.001) formation.
Fig. 2.
Fig. 2.
Changes in BDNF mRNA expression in the hippocampus and frontal cortex of rats associated with spatial memory formation. Rats were trained for the reference and working memory task for 28 d. 7-NI was administered every day 60 min before each training trial. Animals were killed immediately, 15, or 30 min after the last training. The levels of BDNF and β-actin were measured by RT-PCR. Representative gel patterns showing BDNF and β-action cDNA bands at different times after training in the hippocampus (A) and frontal cortex (C). The quantitative results of RT-PCR in the hippocampus (B) and frontal cortex (D). The number in parentheses shows the number of animals. The BDNF mRNA level was normalized with the β-action mRNA level. Each value represents the mean ± SE. ***p < 0.001 versus immediately after the training (0 min). ###p< 0.001 versus corresponding vehicle-treated rats.
Fig. 3.
Fig. 3.
Spatial reference (A) and working (B) memory formation in nonoperated control rats (n = 7) and rats that were continuously infused with BDNF antisense (n = 6) and sense oligonucleotides (n = 6) into the cerebral ventricle. The maze training was started 4 d after the start of continuous intracerebroventricular infusion of the oligonucleotide. Each value represents the mean ± SE. Antisense BDNF treatment significantly impaired reference (p < 0.001) and working memory formation (p < 0.001).
Fig. 4.
Fig. 4.
Effects of continuous infusion of BDNF antisense (n = 6) and sense oligonucleotides (n = 6) into the cerebral ventricle on locomotor activity, food consumption, and body weight. Rats were continuously infused with BDNF antisense or sense oligonucleotide into the cerebral ventricle and were subjected to the radial maze test for 21 d. Locomotor activity (A), food consumption (B), and body weight (C) were measured on the day after the last training. Each value represents the mean ± SE.
Fig. 5.
Fig. 5.
Effects of continuous infusion of BDNF antisense and sense oligonucleotides into the cerebral ventricle on BDNF protein (A) and mRNA (B) levels in the hippocampus. Rats were continuously infused with BDNF antisense or sense oligonucleotide into the cerebral ventricle and were subjected to the radial maze test for 21 d. The rats treated with antisense or sense BDNF oligonucleotide and nontrained control rats were killed on the day after the last training for the measurement of BDNF protein (A) and mRNA (B) levels. The number in parentheses shows the number of animals. Each value represents the mean ± SE. *p < 0.05 versus control. #p < 0.05 versus antisense-treated group.
Fig. 6.
Fig. 6.
Effects of continuous infusion of BDNF antisense and sense oligonucleotide into the cerebral ventricle on spatial reference (A) and working (B) memory retention and/or recall in rats which had previously acquired the spatial reference and working memory. Rats were first trained for the reference and working memory task for 28 d and then received a surgical operation for the continuous intracerebroventricular infusion of BDNF antisense (n = 11) or sense oligonucleotide (n = 10). The radial maze test was started 4 d after the start of oligonucleotide treatment. Each value represents the mean ± SE. Antisense BDNF treatment significantly increased the number of reference (p < 0.0001) and working memory errors (p < 0.0001).
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