GABA-receptive microglia selectively sculpt developing inhibitory circuits

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and therefore wiring precision. However, whether the remodeling of distinct synapses during development is mediated by specialized microglia is unknown. Here, using in vivo two-photon imaging, we show that GABA-receptive microglia selectively interact with inhibitory synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to stereotyped repetitive behavior and hyperactivity. These findings demonstrate that distinct microglia differentially engage with specific synapse types during development. Overall design: We performed single cell RNA sequencing (scRNA-seq) of microglia isolated from the somatosensory cortex of postnatal day 15 mice of the following genotypes: wild-type (Cx3cr1+/+; GABAB1Rfl/fl; N = 12; 3 females and 9 males; 2 replicates), Cre-Het controls (Cx3cr1Cre/+; GABAB1R+/+; N = 10; 8 females and 2 males; 1 replicate) and GABAB1R cKO (Cx3cr1Cre/+; GABAB1Rfl/fl; N = 13; 9 females and 4 males; 2 replicates). Single-cell RNA-seq libraries were prepared on the 10x Genomics platform and sequenced using the Nova-Seq 100 cycle kit (Illumina).