Semaphorins and the dynamic regulation of synapse assembly, refinement, and function

Abstract

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.

Figure 1. Semaphorins directly affect synapse formation, altering the balance between excitation and inhibition

(a) Semaphorins and excitatory synaptogenesis. (I) Sema3F inhibits excitatory synapse formation by constraining the density of dendritic spines along apical dendrites of deep layer cortical pyramidal neurons. (II) Sema4B promotes the assembly of glutamatergic synapses in cultured hippocampal neurons. The Sema4B cytoplasmic domain includes a PDZ-binding motif that can associate with PSD-95, possibly mediating assembly of postsynaptic specializations (though this has yet to be demonstrated). (b) Semaphorins and the assembly of inhibitory synapses. (I) Sema4D promotes GABAergic inhibitory synaptogenesis in hippocampal neurons in vitro and in vivo. Sema4D is required in postsynaptic neurons, where it is mainly localized to synapses, both in vitro and in vivo. However, plexin-B1 could act in cis (in the postsynaptic neuron) or in trans (in the presynaptic terminal) to mediate the assembly of inhibitory synapses. Posttranslational proteolytic Sema4D processing occurs in vitro and in vivo but apparently is not required for Sema4D regulation of GABAergic synapse assembly. (II) Sema4B promotes the assembly of inhibitory synapses by affecting postsynaptic specializations.

Figure 2. Electrical activity and chemotropism in synapse refinement in vivo

(a) In Drosophila embryos and larvae, electrical activity in motor neurons renders them more sensitive to the muscle-derived chemorepellent Sema-2a, causing exuberant motor neuron terminals to withdraw and preventing aberrant synapse formation at the Drosophila neuromuscular junction. (b) Null mutations in Sema-2a or (c) ion channels, allow motor neurons to establish ectopic synaptic contacts on somatic muscles that mature into functional synapses. (d) Electrical activity in motor neurons synergizes with the response to Sema2a, mediated by the plexin B receptor (expressed in motor neurons), and regulates formation of neuromuscular junctions. A partial loss of presynaptic activity accompanied by a partial loss of chemorepulsion leads to the formation of ectopic synaptic contacts on muscles. Therefore, electrical activity interacts with Sema-2a–Plexin-B chemorepulsive signaling to increase motor neuron responses to Sema-2a.