Semaphorin 4D induced inhibitory synaptogenesis decreases epileptiform activity and alters progression to Status Epilepticus in mice

Adel, Susannah S.; Clarke, Vernon R. J.; Evans-Strong, Aidan; Maguire, Jamie; Paradis, Suzanne

doi:10.1016/j.eplepsyres.2023.107156

Cited by 3 publications

(2 citation statements)

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“…In addition, recent advances from our group demonstrated the therapeutic potential of targeting GABAergic synapse formation and function in the case of neurological disorders involving hyperexcitability, underscoring the importance of delineating these processes (Acker et al, 2018; Adel et al, 2023). For example, we previously found that application of the Sema4D extracellular domain to neuronal cultures increased GABAergic synapse density within 30 minutes, increased inhibitory tone within 2hrs of application, and increased resistance to seizure in various rodent models of epilepsy (Adel et al, 2023; Kuzirian et al, 2013). The selective, rapid, and functional effects of Sema4D motivated our further investigation into the mechanisms of synapse development mediated by Semaphorin/Plexin signaling.…”

Section: Introductionmentioning

confidence: 97%

“…One exception to this is that Sema4D signaling through its receptor Plexin-B1 regulates GABAergic, but not glutamatergic, synapse formation. We previously demonstrated that application of the extracellular domain of Sema4D either in vitro or in vivo caused the rapid formation (2hrs) of functional, GABAergic synapses (Adel et al, 2023; Kuzirian et al, 2013). Using a live imaging approach, we showed that Sema4D application affects the behavior of GFP-labeled gephyrin which is a postsynaptic scaffolding protein at GABAergic synapses.…”

Section: Introductionmentioning

confidence: 99%

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Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Adel,

Pranske,

Kowalski

et al. 2023

Preprint

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Synapse formation in the mammalian brain is a complex and dynamic process requiring coordinated function of dozens of molecular families such as cell adhesion molecules (CAMs) and ligand-receptor pairs (Ephs/Ephrins, Neuroligins/Neurexins, Semaphorins/Plexins). Due to the large number of molecular players and possible functional redundancies within gene families, it is challenging to determine the precise synaptogenic roles of individual molecules, which is key to understanding the consequences of mutations in these genes for brain function. Furthermore, few molecules are known to exclusively regulate either GABAergic or glutamatergic synapses, and cell and molecular mechanisms underlying GABAergic synapse formation in particular are not thoroughly understood. However, we previously demonstrated that Semaphorin-4D (Sema4D) regulates GABAergic synapse development in the mammalian hippocampus while having no effect on glutamatergic synapse development, and this effect occurs through binding to its high affinity receptor, Plexin-B1. Furthermore, Plexin-B2 contributes to GABAergic synapse formation as well but is not required for GABAergic synapse formation induced by binding to Sema4D. Here, we perform a structure-function study of the Plexin-B1 and Plexin-B2 receptors to identify the protein domains in each receptor that are required for its synaptogenic function. We also provide evidence that Plexin-B2 expression in presynaptic parvalbumin-positive interneurons is required for formation of GABAergic synapses onto excitatory pyramidal neurons in CA1. Our data reveal that Plexin-B1 and Plexin-B2 function non-redundantly to regulate GABAergic synapse formation and suggest that the transmembrane domain may underlie these functional distinctions. These findings lay the groundwork for future investigations into the precise signaling pathways required for synapse formation downstream of Plexin-B receptor signaling.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Adel,

Pranske,

Kowalski

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Adel,

Pranske,

Kowalski

et al. 2024

Molecular and Cellular Neuroscience

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Semaphorin heterodimerization in cis regulates membrane targeting and neocortical wiring

Bessa,

Newman,

Yan

et al. 2024

Nat Commun

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Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.

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Semaphorin 4D induced inhibitory synaptogenesis decreases epileptiform activity and alters progression to Status Epilepticus in mice

Cited by 3 publications

References 46 publications

Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Plexin-B1 and Plexin-B2 play non-redundant roles in GABAergic synapse formation

Semaphorin heterodimerization in cis regulates membrane targeting and neocortical wiring

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