Sema4D localizes to synapses and regulates GABAergic synapse development as a membrane-bound molecule in the mammalian hippocampus

Abstract

While numerous recent advances have contributed to our understanding of excitatory synapse formation, the processes that mediate inhibitory synapse formation remain poorly defined. Previously, we discovered that RNAi-mediated knockdown of a Class 4 Semaphorin, Sema4D, led to a decrease in the density of inhibitory synapses without an apparent effect on excitatory synapse formation. Our current work has led us to new insights about the molecular mechanisms by which Sema4D regulates GABAergic synapse development. Specifically, we report that the extracellular domain of Sema4D is proteolytically cleaved from the surface of neurons. However, despite this cleavage event, Sema4D signals through its extracellular domain as a membrane-bound, synaptically localized protein required in the postsynaptic membrane for proper GABAergic synapse formation. Thus, as Sema4D is one of only a few molecules identified thus far that preferentially regulates GABAergic synapse formation, these findings have important implications for our mechanistic understanding of this process.

Regulation of GABAergic synapse development by postsynaptic membrane proteins

“…In addition, Sema4D is sufficient to promote GABAergic synapse development, as treatment of cultured hippocampal neurons with purified extracellular domain of Sema4D can rapidly induce new GABAergic synapse formation (Kuzirian et al, 2013). Mechanistically, Sema4D signals through binding to its receptor, PlexinB1, to regulate GABAergic synaptogenesis, as the effect of Sema4D treatment in synapse development is lost in neurons prepared from PlexinB1 KO mice (Kuzirian et al, 2013; Raissi et al, 2013). Structurally, Sema4D is a transmembrane protein, which – once targeted to the plasma membrane – can undergo metalloproteinase-mediated cleavage to release its extracellular domain for signaling (Basile et al, 2007).…”

The balancing act of GABAergic synapse organizers

“…The class IV semaphorin Sema4D promotes inhibitory synapse development, working in tandem with its receptor PlexinB1 [49,50]. Tropomyosin-related kinase B (TrkB) contributes to inhibitory synapse assembly by controlling the synaptic localization of gephyrin in a subset of interneurons [51].…”

Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease

“…In addition to axonal guidance and synapse formation (Kuzirian et al, 2013;Raissi et al, 2013), SEMA4D has been shown to play a role in migration and differentiation of neuronal and oligodendrocyte precursor cells, CNS inflammation and neurodegeneration. For example, SEMA4D deficiency leads to increased oligodendrocyte differentiation, whereas exogenously added soluble SEMA4D inhibits oligodendrocyte differentiation (Yamaguchi et al, 2012).…”