Abstract
Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P et al. Molecular cloning and expression of brain-derived neurotrophic factor. Nature 1989; 341: 149–152.
Shors T, Matzel L . Long-term potentiation: what's learning got to do with it. Behav Brain Sci 1997; 20: 597–655.
Yamada K, Mizuno M, Nabeshima T . Role for brain-derived neurotrophic factor in learning and memory. Life Sci 2002; 70: 735–744.
Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T . Involvement of brain-derived neurotrophic factor is spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 2000; 20: 7116–7121.
Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B . Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 1999; 6: 243–256.
Segal RA, Greenberg ME . Intracellular signaling pathway activated by neurotrophic factors. Annu Rev Neurosci 1996; 19: 463–489.
Skaper SD, Walsh FS . Neurotrophic molecules: strategies for designing effective therapeutic molecules in neurodegeneration. Mol Cell Neurosci 1998; 12: 179–193.
He J, Yamada K, Nabeshima T . A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 2002; 26: 259–268.
Downward J . Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10: 262–267.
Yamada M, Ohnishi H, Sano S, Araki T, Nakatani A, Ikeuchi T et al. Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons. J Neurochem 1999; 73: 41–49.
Kang H, Schuman MA . Requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 1996; 273: 1402–1406.
Takei N, Kawamura M, Hara K, Yonezawa K, Nawa H . Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin. J Biol Chem 2001; 276: 42 818–42 825.
Pain VM . Initiation of protein synthesis in eukaryotic cells. Eur J Biochem 1996; 236: 747–771.
Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N . 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt (PKB) signaling pathway. Genes Dev 1998; 12: 502–513.
Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13: 1422–1437.
Proud CG . Protein phosphorylation in translational control. Curr Topics Cell Regul 1992; 32: 243–369.
Proud CG . Peptide chain elongation in eukaryotes. Mol Biol Rep 1994; 19: 161–170.
Beretta L, Gingras AC, Svitkin YV, Hall MN, Sonenberg N . Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 1996; 15: 658–664.
Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 1997; 272: 26 457–26 463.
McAllister AK, Katz LC, Lo DC . Neurotrophins and synaptic plasticity. Annu Rev Neurosci 1999; 22: 295–318.
Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Swett JD . The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1998; 1: 602–609.
Blum S, Moore AN, Adams F, Dash PK . A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999; 19: 3535–3544.
Selcher JC, Atkins CM, Trzaskos JM, Paylor R, Swett JD . A necessity for MAP kinase activation in mammalian spatial learning. Learn Mem 1999; 6: 478–490.
Impey S, Obrietan K, Storm DR . Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23: 11–14.
Blum S, Moore AN, Adams F, Dash PK . A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999; 19: 3535–3544.
Tsien JZ, Huerta PT, Tonegawa S . The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 1996; 87: 1327–1338.
Kelly A, Lynch MA . Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin. Neuropharmacology 2000; 39: 643–651.
Ying S-W, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TVP et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: Requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 2002; 22: 1532–1540.
Paxinos G, Watson C . The rat brain in stereotaxic coordinates. Academic Press: New York, 1982.
Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 1995; 374: 450–453.
Acknowledgements
We thank Dr Joseph T Coyle for valuable comments and suggestions. This study was supported in part by a Grant-in-Aid for Scientific Research (Nos. 14370031 and 14658249), and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program, from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mizuno, M., Yamada, K., Takei, N. et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatry 8, 217–224 (2003). https://doi.org/10.1038/sj.mp.4001215
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001215
Keywords
This article is cited by
-
(m) RVD-hemopressin (α) Ameliorated Oxidative Stress, Apoptosis and Damage to the BDNF/TrkB/Akt Pathway Induced by Scopolamine in HT22 Cells
Neurotoxicity Research (2023)
-
Clathrin-nanoparticles deliver BDNF to hippocampus and enhance neurogenesis, synaptogenesis and cognition in HIV/neuroAIDS mouse model
Communications Biology (2022)
-
A Skate Skin Hydrolysate Restores Cognitive Function in 5XFAD Alzheimer Disease Mice Model by Suppressing Amyloid-β Accumulation via Upregulation of ERK-CREB
International Journal of Peptide Research and Therapeutics (2021)
-
Eclalbasaponin II Ameliorates the Cognitive Impairment Induced by Cholinergic Blockade in Mice
Neurochemical Research (2018)
-
Glucosyltransferase Activity of Clostridium difficile Toxin B Triggers Autophagy-mediated Cell Growth Arrest
Scientific Reports (2017)