Molecular pathway underlying bouton stabilization by Semaphorin4D during inhibitory synapse formation.

Changes in inhibitory connections are essential for experience-dependent circuit adaptations, and inhibitory defects may underlie neurodevelopmental diseases such as autism. Inhibitory axons and their presynaptic boutons can undergo rapid changes, but the molecular mechanisms underlying these dynamics and their role in inhibitory synapse formation are currently unclear. By monitoring inhibitory axons over time in organotypic hippocampal slices, we show that stabilization of presynaptic boutons is the first step in inhibitory synapse formation and that this process is regulated by the guidance protein Semaphorin4D (Sema4D). Sema4D signaling induces inhibitory bouton stabilization within tens of minutes without affecting bouton disassembly. We show that this signaling pathway requires ongoing neuronal activity, and involves activation of receptor tyrosine kinase MET and actin remodeling. Our data indicate that actin plays an important role during synapse formation and demonstrate a novel link between MET, a known autism risk factor, and inhibitory presynaptic dynamics.