Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior

Takashi Komori, Kazuya Okamura, Minobu Ikehara, Kazuhiko Yamamuro, Nozomi Endo, Kazuki Okumura, Takahira Yamauchi, Daisuke Ikawa, Noriko Ouji-Sageshima, Michihiro Toritsuka, Ryohei Takada, Yoshinori Kayashima, Rio Ishida, Yuki Mori, Kohei Kamikawa, Yuki Noriyama, Yuki Nishi, Toshihiro Ito, Yasuhiko Saito, Mayumi NishiToshifumi Kishimoto, Kenji F. Tanaka, Noboru Hiroi, Manabu Makinodan

Producción científica: Articlerevisión exhaustiva

Resumen

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors—associated with the medial prefrontal cortex (mPFC)—has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21–p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf—regulated using doxycycline at different time points—underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45–p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.

Idioma originalEnglish (US)
Páginas (desde-hasta)1338-1349
Número de páginas12
PublicaciónMolecular psychiatry
Volumen29
N.º5
DOI
EstadoPublished - may 2024

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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