TY - JOUR
T1 - Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior
AU - Komori, Takashi
AU - Okamura, Kazuya
AU - Ikehara, Minobu
AU - Yamamuro, Kazuhiko
AU - Endo, Nozomi
AU - Okumura, Kazuki
AU - Yamauchi, Takahira
AU - Ikawa, Daisuke
AU - Ouji-Sageshima, Noriko
AU - Toritsuka, Michihiro
AU - Takada, Ryohei
AU - Kayashima, Yoshinori
AU - Ishida, Rio
AU - Mori, Yuki
AU - Kamikawa, Kohei
AU - Noriyama, Yuki
AU - Nishi, Yuki
AU - Ito, Toshihiro
AU - Saito, Yasuhiko
AU - Nishi, Mayumi
AU - Kishimoto, Toshifumi
AU - Tanaka, Kenji F.
AU - Hiroi, Noboru
AU - Makinodan, Manabu
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-024-02413-y
DO - 10.1038/s41380-024-02413-y
M3 - Article
C2 - 38243072
AN - SCOPUS:85182678663
SN - 1359-4184
VL - 29
SP - 1338
EP - 1349
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 5
ER -