The highly localized interaction between Neurofascin-186 and Gliomedin promotes subcellular innervation by the chandelier cell

A variety of cortical inhibitory interneuron (IN) subtypes differentially but coordinately operate in local circuits to process neuronal signals. The subcellular arrangement of IN synaptic outputs contributes to subtype-specific functional specialization. However, it remains poorly understood what intercellular molecular interactions enable the matched synapse formation between IN subtypes and specific subcellular domains. Using mice of both sexes, we demonstrate that Neurofascin-186 (NF186), a cell adhesion molecule specifically expressed in the axon initial segments (AISs) of pyramidal neurons, is necessary for chandelier cells (ChCs) to develop a string of synaptic boutons along the AIS (an axon cartridge). Furthermore, we discovered that Gliomedin, a known receptor for NF186 in the nodes of Ranvier, is preferentially expressed in ChCs and mediates ChC axon cartridge development by acting as a major receptor for NF186. Thus, the intercellular interaction through subcellularly-restricted ligands and cell type-specific receptors ensures a high degree of IN subcellular synapse specificity. Significance Statement Inhibitory regulations by cortical interneurons (cINs) play a critical role in exquisite brain computations. The subcellular synapse specificity of cINs is one pivotal determinant for their output properties. However, the underlying molecular mechanisms remain poorly understood. The present study demonstrates that Gliomedin and Neurofascin-186 are preferentially localized to the chandelier cell (ChC), one cIN subtype, and the axon initial segment (AIS) of the pyramidal neuron, the subcellular synaptic target of ChCs, respectively and serve as a ligand-receptor pair that mediates AIS innervation by ChCs. These findings substantiate the concept that the subcellular molecular tags recognized by the cIN subtype specific receptors play a key role in establishing cIN subcellular synapse specificity.