Class 4 Semaphorins and Plexin-B receptors mediate synapse development and have therapeutic potential in epilepsy
Creators: name: Adel, Susannah
Publisher: name: Brandeis University
Year: 2025
Subjects: Plexin receptor
Semaphorin
synapse development
Epilepsy

description: Proper circuit function in the mammalian brain relies upon cell-cell communication through two main types of chemical synapses: glutamatergic (excitatory) and GABAergic (inhibitory). Formation of these synapses requires coordinated action of numerous synaptogenic molecular families such as cell adhesion molecules and ligand/receptor pairs. These genes designate the proper location of nascent synaptic sites, cluster the required pre- and postsynaptic machinery, and ultimately modify synapse strength and function. Synapse dysfunction, and in particular the improper balance between excitatory and inhibitory synaptic inputs, is highly correlated with a variety of neurological disorders; i.e. epilepsy, autism, and schizophrenia. In order to develop therapeutics for synaptopathies, it is critical to understand how divergent mechanisms instruct formation of either a glutamatergic or GABAergic synapse. However, very few molecules have been identified as selective regulators of GABAergic synapse development. In the past decade, we revealed that the axon guidance molecule, Semaphorin 4D exclusively promotes formation of GABAergic synapses by signaling to its receptor, Plexin-B1, and furthermore that Plexin-B2 (another Plexin-B family member) regulates GABAergic synapse formation in the mammalian hippocampus. In part one of this work, we aim to delineate the precise requirements for molecular motifs of Plexin-B1 and Plexin-B2 receptors that underlie their synaptogenic functions. First, we establish that Plexin-B1 and Plexin-B2 do not function redundantly in GABAergic synapse development by showing that molecular compensation does not occur between the two upon Plexin-B1 deletion. We then provide evidence that Plexin-B2 expression in presynaptic parvalbumin-positive interneurons is required for formation of GABAergic synapses onto excitatory pyramidal neurons in CA1. Next, we perform a genetic dissection of Plexin-B1 and Plexin-B2 by engineering chimeric Plexin-B proteins with molecular domain swaps between Plexin-B1 and Plexin-B2 and assaying for their abilities to instruct synaptogenesis. Our data reveal that Plexin-B1 and Plexin-B2 major signaling motifs are functionally distinct in the context of GABAergic synapse formation. Next, we explore therapeutic applications of increasing GABAergic synapse formation. We previously demonstrated that delivery of recombinant Sema4D to the hippocampus provides protective effects against seizure in a mouse model of epilepsy. Here, we follow up on this finding by 1) validating a more practical gene therapy approach for delivery of Sema4D, and 2) demonstrating its therapeutic effects in a rodent model of a severe drug-resistant form of epilepsy, Status epilepticus. These studies together inform the molecular signaling pathways that instruct formation of GABAergic synapses, as well as establish the therapeutic potential for gene therapies upregulating GABAergic synapses in the hippocampus.