BDNF function and intracellular signaling in neurons
Tadahiro Numakawa1, Shingo Suzuki2,3, Emi Kumamaru1, Naoki Adachi1,4, Misty Richards1,5 and Hiroshi Kunugi1,4
1Deparment of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan, 2Medical Top Track (MTT) Program, Medical Research Institute, Tokyo Medical and Dental University, 3Department of Molecular Neuroscience, Medical Rsearch Institute, Tokyo Medical and Dental University, 4CREST, JST, Saitama and 5Albany Medical College, Albany, USA.
Offprint requests to: Tadahiro Numakawa, Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokio 187-8502, Japan. e-mail: email@example.com
Summary. Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are broadly expressed in the developing and adult mammalian brain. BDNF/TrkB-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, and plasticity. It is well known that binding of BDNF to TrkB elicits various intracellular signaling pathways, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), phospholipase Cγ (PLCγ), and phosphoinositide 3-kinase (PI3K) pathways, and that BDNF exerts biological effects on neurons via activation of similar mechanisms. In addition to TrkB, a low-affinity receptor p75 is also involved in neuronal survival and plasticity. BDNF affects neurons positively or negatively through various intracellular signaling pathways triggered by activation of TrkB or p75. From a clinical standpoint, roles of BDNF have been implicated in the pathophysiology of various brain diseases. The stress-induced steroid hormone, glucocorticoid, and BDNF are putatively associated with the pathophysiology of depression. Recent reports, including our studies, demonstrate possible crosstalk between glucocorticoid- and BDNF/TrkB-mediated signaling. Here, we present a broad overview of the current knowledge concerning BDNF action and associated intracellular signaling as it relates to neuronal protection, synaptic function, and morphological change. Furthermore, understanding the secretion and intracellular dynamics of BDNF proteins is critical as the fate of secreted BDNF may contribute to differences in neuronal response. Histol Histopathol 25, 237-258 (2010)
Key words: Synaptic function, Morphological changes, Cholesterol metabolism, Mental illness, BDNF regulator, BDNF secretion