Semaphorins are phylogenetically conserved proteins expressed in most organ systems, including the nervous system. Following their description as axon guidance cues, semaphorins have been implicated in multiple aspects of nervous system development. Semaphorins are key regulators of neural circuit assembly, neuronal morphogenesis, assembly of excitatory and inhibitory synapses, and synaptic refinement. Semaphorins contribute to the balance between excitatory and inhibitory synaptic transmission, and electrical activity can modulate semaphorin signaling in neurons. This interplay between guidance cue signaling and electrical activity has the potential to sculpt the wiring of neural circuits and to modulate their function.
SUMMARY
Regulation of AMPA-type glutamate receptor (AMPAR) number at synapses is a major mechanism for controlling synaptic strength during homeostatic scaling in response to global changes in neural activity. We show that the secreted guidance cue semaphorin 3F (Sema3F) and its neuropilin-2 (Npn-2)/plexinA3 (PlexA3) holoreceptor mediate homeostatic plasticity in cortical neurons. Sema3F-Npn-2/PlexA3 signaling is essential for cell surface AMPAR homeostatic downscaling in response to an increase in neuronal activity, Npn-2 associates with AMPARs, and Sema3F regulates this interaction. Therefore, Sema3F-Npn-2/PlexA3 signaling controls both synapse development and synaptic plasticity.
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