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

Microglia and brain-derived neurotrophic factor (BDNF) are essential for neuroplasticity during critical developmental periods. Social behaviors associated with the medial prefrontal cortex (mPFC) develop during a juvenile critical period in mice. Whether microglia and BDNF affect social development remains unclear. Here, we investigated the effects of microglia-derived BDNF (MG-BDNF) on social behaviors and mPFC development. Juvenile social isolation (p21–p35) increased Bdnf in microglia and reduced adulthood sociability. Using transgenic mice with microglial Bdnf overexpression regulated by doxycycline at different time points, we conducted behavioral, electrophysiological, and gene expression analyses. Long-term MG-BDNF overexpression impaired sociability and produced excessive inhibitory neuronal circuit activity in the mPFC. Normalizing BDNF from p21 restored sociability and electrophysiological function, whereas normalizing from later ages (p45–p60) did not normalize excitatory/inhibitory dynamics in the mPFC despite sociability improvement. To evaluate relevance to human sociability, adverse childhood experiences were correlated with BDNF expression in human macrophages, showing a positive relationship between childhood experiences/BDNF and mPFC function, particularly during the juvenile period. These findings suggest a potential translational link between MG-BDNF and childhood experiences in humans.

Takashi Komori, Kazuya Okamura, Inhibou 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 Kanemkawa, Yuki Noriyama, Yuki Nishi, Toshihiro Ito, Yasuhiko Saito, Mayumi Nishi, Toshifumi Kishimoto, Fumiaki Tanaka, Noboru Hori, Manabu Makino