GABA-receptive microglia selectively sculpt developing inhibitory circuits

• Published in: Cell Vol. 184; no. 15; pp. 4048 - 4063.e32
• Main Authors: Favuzzi, Emilia, Huang, Shuhan, Saldi, Giuseppe A., Binan, Loïc, Ibrahim, Leena A., Fernández-Otero, Marian, Cao, Yuqing, Zeine, Ayman, Sefah, Adwoa, Zheng, Karen, Xu, Qing, Khlestova, Elizaveta, Farhi, Samouil L., Bonneau, Richard, Datta, Sandeep Robert, Stevens, Beth, Fishell, Gord
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2021
• Subjects: Animals; Animals, Newborn; Behavior, Animal; cerebral cortex; development; gamma-Aminobutyric Acid - metabolism; Gene Expression Regulation; glia-neuron interactions; HEK293 Cells; Humans; inhibitory synapses; interneurons; Mice; microglia; Microglia - metabolism; Neural Inhibition - physiology; neurodevelopmental disorders; Parvalbumins - metabolism; Phenotype; Receptors, GABA-B - metabolism; Synapses - physiology; Transcription, Genetic; cerebral cortex; inhibitory synapses; development; glia-neuron interactions; microglia; neurodevelopmental disorders; interneurons
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.06.018

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical 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 behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types. [Display omitted] •GABA-receptive microglia interact with inhibitory synapses during development•Removing GABABRs from microglia alters inhibitory but not excitatory connectivity•Synapse pruning genes are altered in GABA-receptive microglia lacking GABABRs•Mice lacking microglial GABAB1Rs exhibit behavioral abnormalities GABA-receptive microglia selectively prune inhibitory synapses in development and disruption of this microglial response leads to behavioral abnormalities highlighting a critical function of selective communication between microglia and neuronal cell types.