Involvement of Brain-Derived Neurotrophic Factor in Spatial Memory Formation and Maintenance in a Radial Arm Maze Test in Rats

Abstract

Brain-derived neurotrophic factor (BDNF) regulates both shortterm 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.

A Role of Fos Expression in the CA3 Region of the Hippocampus in Spatial Memory Formation in Rats

“…We have been using the reference/working memory task in the radial arm maze to clarify the neuronal mechanisms of each category of memory (Zou et al 1998(Zou et al , 1999Mizuno et al 2000). The antisense c-fos oligonucleotide treatment into the dorsal hippocampus impaired not only long-term memory (reference memory) but also short-term working memory (Figure 4).…”

“…Rats ( n ϭ 9) were trained for the reference/working memory task, five trials per day for 5 days, as described previously (Zou et al 1998(Zou et al , 1999Mizuno et al 2000). Briefly, rats were well handled for 3 days in their home cages and then shaped for 4 days in the maze to run to the end of the arms and consume the bait, in groups of four rats.…”

“…For comparison, two additional groups, the naive and sham-trained control groups, were prepared. The sham-trained control group was kept on a restricted diet, as were the trained animals, put on the radial arm maze everyday without actual maze training, and given four food pellets in every sham-training trial (Mizuno et al 2000).…”

“…26 , NO . 2 ing-associated changes in Fos expression in rats that were subjected to the reference/working memory task with an eight-arm radial maze (Zou et al 1998(Zou et al , 1999Mizuno et al 2000). Furthermore, to examine the possible causal relation between Fos expression and memory formation, we investigated the effects of an antisense oligonucleotide treatment directed against c-fos mRNA on spatial memory formation.…”

Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation

“…The binding of Brain-derived neurotrophic factor (BDNF) [1][2][3][4] to its receptor tyrosine kinase B (TrkB) leads to autophosphorylation of tyrosine residues in the intracellular domain of the receptor and subsequent activation of cytoplasmic signaling pathways. Tyrosine phosphorylated TrkB serves as a scaffold for the recruitment of adaptor proteins and enzymes, including mitogen-associated protein kinase (MAPK), phospholipase C-g (PLC-g) and PI3-K that further transduce the BDNF signal.…”