Neurochemical Research

, Volume 39, Issue 4, pp 785–792

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

  • Tadahiro Numakawa
  • Tomoya Matsumoto
  • Yoshiko Ooshima
  • Shuichi Chiba
  • Miyako Furuta
  • Aiko Izumi
  • Midori Ninomiya-Baba
  • Haruki Odaka
  • Kazuo Hashido
  • Naoki Adachi
  • Hiroshi Kunugi
Original Paper

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.

Keywords

Schizophrenia Intrauterine growth retardation BDNF TrkB Glutamatergic transmission 

Supplementary material

11064_2014_1270_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1571 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Tadahiro Numakawa
    • 1
    • 2
  • Tomoya Matsumoto
    • 2
    • 3
  • Yoshiko Ooshima
    • 1
  • Shuichi Chiba
    • 1
    • 4
  • Miyako Furuta
    • 1
    • 5
  • Aiko Izumi
    • 1
    • 6
  • Midori Ninomiya-Baba
    • 1
    • 7
  • Haruki Odaka
    • 1
    • 8
  • Kazuo Hashido
    • 9
  • Naoki Adachi
    • 1
    • 2
  • Hiroshi Kunugi
    • 1
    • 2
  1. 1.Department of Mental Disorder Research, National Institute of NeuroscienceNational Center of Neurology and PsychiatryKodairaJapan
  2. 2.Core Research for Evolutional Science and Technology (CREST)Japan Science and Technology Corporation (JST)KawaguchiJapan
  3. 3.Department of Psychiatry and Neurosciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  4. 4.Faculty of Pharmacy, Research Institute of Pharmaceutical ScienceMusashino UniversityNishi-TokyoJapan
  5. 5.Department of PhysiologySt Marianna University School of MedicineKawasakiJapan
  6. 6.Division of Structural Cell BiologyNara Institute of Science and TechnologyIkomaJapan
  7. 7.Department of Pharmacology, Graduate School of Advanced Science and EngineeringWaseda UniversityShinjuku-kuJapan
  8. 8.Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and EngineeringWaseda UniversityShinjuku-kuJapan
  9. 9.Administrative Section of Radiation Protection, National Institute of NeuroscienceNational Center of Neurology and PsychiatryKodairaJapan

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