Microglia regulate chandelier cell axo-axonic synaptogenesis

Microglia have emerged as critical regulators of synapse development and circuit formation in the healthy brain. To date, examination of microglia in such processes has largely been focused on excitatory synapses. Their roles, however, in the modulation of GABAergic interneuron synapses—particularly those targeting the axon initial segment (AIS)—during development remain enigmatic. Here, we identify a synaptogenic/growth-promoting role for microglia in regulating pyramidal neuron (PyN) AIS synapse formation by chandelier cells (ChCs), a unique interneuron subtype whose axonal terminals, called cartridges, selectively target the AIS. We show that a subset of microglia contacts PyN AISs and ChC cartridges and that such tripartite interactions, which rely on the unique AIS cytoskeleton and microglial GABA(B1) receptors, are associated with increased ChC cartridge length and bouton number and AIS synaptogenesis. Conversely, microglia depletion or disease-induced aberrant microglia activation impairs the proper development and maintenance of ChC cartridges and boutons, as well as AIS synaptogenesis. These findings unveil key roles for homeostatic, AIS-associated microglia in regulating proper ChC axonal morphogenesis and synaptic connectivity in the neocortex.