Microglia's role in activity-dependent synapse refinement and brain circuit formation is crucial for normal brain development. A critical period exists for postnatal development, where neural network plasticity is heightened, enabling experience-dependent circuit reorganization. Microglia's involvement in this critical-period plasticity is increasingly recognized. Social behaviors also undergo experience-dependent maturation within a limited postnatal window. Social deprivation during this period negatively impacts the medial prefrontal cortex (mPFC), a key region for social behavior regulation. Previous research implicated microglia in juvenile social isolation and subsequent social impairment. Brain-derived neurotrophic factor (BDNF), secreted by microglia, contributes to maintaining inhibitory interneurons and closing critical periods. However, the influence of microglia-secreted BDNF (MG-BDNF) on cortical critical-period plasticity remained unclear. This study aimed to investigate the time-specific effects of microglial BDNF on mPFC biology and social behavior.

Existing literature highlights the crucial role of microglia in activity-dependent brain development and synaptic plasticity. Studies have shown that microglia actively participate in synaptic pruning and the formation of neural circuits. The critical period for neural plasticity, characterized by heightened sensitivity to environmental influences, has been extensively studied in sensory cortices. Recent research suggests microglia's significant role in this critical-period plasticity. Similar to sensory functions, social behavior development is also experience-dependent, occurring during a specific postnatal window. Juvenile social deprivation has been linked to alterations in mPFC neural circuits and glial cells, impacting social behavior in adulthood. Studies have implicated microglia in this process. BDNF, a key neurotrophic factor secreted by microglia, contributes to synaptic plasticity and the maintenance of inhibitory interneurons, potentially influencing critical period closure. However, the specific role of microglia-derived BDNF in social development remained poorly understood before this study.

The study used C57BL/6J mice, with a juvenile social isolation (j-SI) group and a group-housed (GH) control group. j-SI mice were isolated from weaning (p21) for two weeks, then re-housed. Behavioral tests (three-chamber social preference test and an augmented reality-based long-term animal behavior observation system) assessed sociability. Microglial BDNF expression was measured using RT-qPCR and ELISA. Microglia-specific BDNF overexpression transgenic mice (Iba1-tTA::Bdnf-oe/+) were generated to investigate the causal link between MG-BDNF and social behavior. Doxycycline (DOX) was used to temporally control BDNF overexpression, administered at different time points (p21 or p45-p60). Electrophysiological analyses (whole-cell patch-clamp recordings) of mPFC layer V pyramidal cells were conducted to assess neuronal excitability and synaptic inputs. RNA-sequencing analyzed gene expression changes in the mPFC. Human peripheral blood mononuclear cells were differentiated into M2 macrophages, and BDNF expression was correlated with adverse childhood experiences (assessed using the Child Abuse and Trauma Scale). Statistical analyses included t-tests, ANOVA, Mann-Whitney U tests, and Spearman's rank correlation.

Juvenile social isolation (j-SI) in mice increased microglial BDNF mRNA expression in the cerebral and prefrontal cortex, correlating with reduced sociability in adulthood. Sustained overexpression of MG-BDNF, using transgenic mice, impaired sociability and increased inhibitory neuronal circuit activity in the mPFC. Electrophysiological recordings showed reduced excitability of mPFC pyramidal neurons in MG-BDNF overexpressing mice, with altered spontaneous excitatory and inhibitory postsynaptic currents. RNA sequencing revealed altered gene expression related to Wnt signaling and the complement system in the mPFC of transgenic mice. Normalizing MG-BDNF overexpression from p21 rescued impaired sociability and normalized electrophysiological and gene expression changes in the mPFC. However, normalizing MG-BDNF from p45-p60 improved sociability but did not fully restore mPFC excitatory/inhibitory balance. In humans, a positive correlation was found between adverse childhood experiences and BDNF expression in M2 macrophages, potentially linking microglial BDNF and childhood experiences.

This study demonstrates a critical role for MG-BDNF in the development of social behaviors and mPFC function in a time-specific manner. The findings suggest that elevated MG-BDNF during the juvenile period may contribute to social deficits through alterations in mPFC neuronal excitability and synaptic function, potentially via modulation of the complement system. The time-sensitive effect of MG-BDNF on mPFC development highlights the importance of early interventions to mitigate the long-term consequences of adverse experiences. The correlation between adverse childhood experiences and BDNF expression in human macrophages suggests a translational relevance, emphasizing the potential of targeting microglial BDNF pathways in treating social deficits associated with early-life adversity.

This study highlights the critical role of MG-BDNF in the development of social behaviors and mPFC function, particularly during the juvenile period. Timely normalization of MG-BDNF expression is crucial for restoring normal social behavior and mPFC function. Future research should explore the precise mechanisms underlying the interaction between MG-BDNF, the complement system, and mPFC development, focusing on the development of targeted therapeutic interventions.

The study used transgenic mice, which might not fully capture the complexity of natural variations in MG-BDNF. The correlation between human macrophage BDNF and childhood trauma is observational, and causality remains to be definitively established. The study focused primarily on the mPFC and did not investigate other brain regions. Further research is needed to explore the role of astrocytic BDNF and the specific impact of MG-BDNF on other brain regions.