Rescuing prefrontal cortical excitation-inhibition imbalance with early-life microglial ablation ameliorates ASD-like behaviors in male BTBR mice.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside the presence of restricted and repetitive behaviors. Microglia, the resident immune cells of the central nervous system, play a crucial role in the development of ASD by regulating synaptic development and plasticity. In this study, we investigate the pharmacological effects and underlying cellular mechanisms of PLX3397 (PLX), a selective inhibitor of the colony-stimulating factor 1 receptor (CSF1R), for the pharmacological ablation of microglia in the context of ASD treatment. Our findings indicate that early postnatal treatment with PLX can enhance social abilities and reciprocal social behaviors while reducing repetitive and stereotyped autism-like behaviors, such as excessive grooming and marble burying. RNA sequencing analysis demonstrated that the neuroprotective effects of PLX are associated with reduced glutamatergic synaptic activity. This is further supported by the observation that PLX decreased vesicular glutamate transporter 1 (vGLUT1) expression, a marker of excitatory presynapses in the medial prefrontal cortex (mPFC). Additionally, we observed a reduction in dendritic spines and inhibition of excitatory synaptic transmission in the pyramidal neurons of the BTBR T + Itpr3tf/J (BTBR) mouse mPFC following early postnatal microglial depletion. Our findings highlight the therapeutic potential of PLX and provide valuable insights into the role of glutamatergic synapses in ASD.