Semaphorin4D induces inhibitory synapse formation by rapid stabilization of presynaptic boutons via MET co-activation

Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus

“…The Sema4D—Plexin-B1 interaction could then generate a trans-synaptic signal that subsequently induces development of the postsynaptic specialization of GABAergic synapses. Our model is also in agreement with a study from the Wierenga group, which recently showed that Sema4D treatment stabilizes inhibitory presynaptic boutons in organotypic hippocampal slices using time-lapse imaging of GFP-labelled GABAergic boutons (Frias et al, 2018).…”

“…Moreover, while treatment with the soluble extracellular domain of Sema4D can promote the development of inhibitory synapses in a Plexin-B1 dependent manner (Kuzirian et al, 2013), the identity of the neuronal subtype(s) which require the function of Plexin-B1 for this process remains an open question. Interestingly, a recent study suggested a potential presynaptic site of action for Plexin-B1, as treatment of organotypic hippocampal slices with the soluble extracellular domain of Sema4D stabilizes presynaptic boutons of GFP-labeled GABAergic axons (Frias et al, 2018). Our previous work also suggested a potential postsynaptic function for Plexin-B1, as treatment of cultured hippocampal neurons with soluble extracellular domain of Sema4D triggers the rapid addition of new postsynaptic assemblies of gephyrin scaffolding proteins, through the splitting of pre-existing assemblies (Kuzirian et al, 2013).…”

Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo

“…These data are consistent with a recent time-lapse imaging study demonstrating that Sema4D application promotes the stabilization of GABAergic presynaptic boutons in hippocampal slice. 21 Taken together, these data suggest that Sema4D promotes the formation of new GABAergic synapses in the mouse hippocampus in vivo, most likely by stabilizing nascent presynaptic boutons.…”

“…5 Time-lapse imaging studies of GAD65-GFP-labeled presynaptic boutons in organotypic hippocampal slice demonstrate that boutons are dynamic structures that appear, disappear, and reappear within a time frame of a few hours. 21,26,27 Of interest, Sema4D treatment promotes the stabilization of a subpopulation of these dynamic boutons, suggesting a mechanism by which Sema4D increases the density of GABAergic boutons. 21 We posit that a population of presynaptic boutons undergo similar dynamics in the adult hippocampus in vivo and that Sema4D treatment promotes the stabilization and subsequent maturation of these boutons.…”

“…21,26,27 Of interest, Sema4D treatment promotes the stabilization of a subpopulation of these dynamic boutons, suggesting a mechanism by which Sema4D increases the density of GABAergic boutons. 21 We posit that a population of presynaptic boutons undergo similar dynamics in the adult hippocampus in vivo and that Sema4D treatment promotes the stabilization and subsequent maturation of these boutons. Furthermore, we postulate that Sema4Ddependent stabilization of presynaptic GABAergic boutons ultimately leads to increased density of functional, GABAergic synapses as GABA receptors and other components of the GABAergic postsynaptic specialization are recruited to newly stabilized boutons.…”