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

Author:

Makinodan Manabu1ORCID,Komori Takashi,Okamura Kazuya,Ikehara Minobu,Yamamuro Kazuhiko,Endo Nozomi,Okumura Kazuki,Yamauchi Takahira,Ikawa Daisuke2,Ouji-Sageshima Noriko,Toritsuka Michihiro2,Takada Ryohei,Kayashima Yoshinori,Ishida Rio,Mori Yuki,Kamikawa Kohei,Noriyama Yuki,Nishi Yuki,Ito T,Saito Yasuhiko,Nishi Mayumi,Kishimoto Toshifumi,Tanaka Kenji3ORCID,Hiroi Noboru4ORCID

Affiliation:

1. Nara Medical University

2. Nara Medical University School of Medicine

3. Keio University School of Medicine

4. University of Texas Health Science Center at San Antonio

Abstract

Abstract 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 microglia Bdnf—regulated using doxycycline at different time points—underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglia BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administration of doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological functions; this was not observed when BDNF was normalized from a later age (p45–p50). 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 substitute for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. Thus, microglia BDNF might regulate sociability and mPFC maturation in mice during the juvenile period. Furthermore, childhood experiences in humans may be related to BDNF secretion from macrophages.

Publisher

Research Square Platform LLC

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