title: Impairments in brain-derived neurotrophic factor-induced glutamate release in cultured cortical neurons derived from rats with intrauterine growth retardation: possible involvement of suppression of TrkB/phospholipase C-γ activation.
abstract: Low birth weight due to intrauterine growth retardation (IUGR) is suggested to be a risk factor for various psychiatric disorders such as schizophrenia. It has been reported that developmental cortical dysfunction and neurocognitive deficits are observed in individuals with IUGR, however, the underlying molecular mechanisms have yet to be elucidated. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with schizophrenia and play a role in cortical development. We previously demonstrated that BDNF induced glutamate release through activation of the TrkB/phospholipase C-γ (PLC-γ) pathway in developing cultured cortical neurons, and that, using a rat model for IUGR caused by maternal administration of thromboxane A2, cortical levels of TrkB were significantly reduced in IUGR rats at birth. These studies prompted us to hypothesize that TrkB reduction in IUGR cortex led to impairment of BDNF-dependent glutamatergic neurotransmission. In the present study, we found that BDNF-induced glutamate release was strongly impaired in cultured IUGR cortical neurons where TrkB reduction was maintained. Impairment of BDNF-induced glutamate release in IUGR neurons was ameliorated by transfection of human TrkB (hTrkB). Although BDNF-stimulated phosphorylation of TrkB and of PLC-γ was decreased in IUGR neurons, the hTrkB transfection recovered the deficits in their phosphorylation. These results suggest that TrkB reduction causes impairment of BDNF-stimulated glutamatergic function via suppression of TrkB/PLC-γ activation in IUGR cortical neurons. Our findings provide molecular insights into how IUGR links to downregulation of BDNF function in the cortex, which might be involved in the development of IUGR-related diseases such as schizophrenia.
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan, numakawa@ncnp.go.jp.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ooshima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Chiba
authors.forename: Miyako
authors.initials: M
authors.lastname: Furuta
authors.forename: Aiko
authors.initials: A
authors.lastname: Izumi
authors.forename: Midori
authors.initials: M
authors.lastname: Ninomiya-Baba
authors.forename: Haruki
authors.initials: H
authors.lastname: Odaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hashido
authors.forename: Naoki
authors.initials: N
authors.lastname: Adachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018698:Glutamic Acid; D020813:Receptor, trkB; D051966:Phospholipase C gamma