# Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2022 · $571,226

## Abstract

We propose to harness the synaptogenic potential of Sema4D signaling to increase
GABAergic synapse number, thus enhancing inhibition in neural circuits and suppressing
seizures. This approach could be beneficial to preventing the establishment of epilepsy, halting
its progression, or suppressing hyperexcitability during a seizure event.
 Previously our lab discovered that the extracellular domain of transmembrane protein
Semaphorin 4D (Sema4D) drives inhibitory synapse formation on a remarkably fast time scale
(i.e. minutes) in hippocampal neurons and slice cultured from the pre-natal and neonatal
hippocampus. We also demonstrated that intra-hippocampal infusion of purified, Sema4D
extracellular domain into the adult hippocampus rapidly promotes the formation of new
GABAergic synapses. Further, we reported that Sema4D treatment protects against seizures
induced by electrical stimulation of the dentate gyrus or by intravenous infusion of the
proconvulsant drug pentylenetetrazol.
 Given the success of these studies, we undertook a new experimental direction to
determine if Sema4D treatment has therapeutic potential for human epilepsies. The first aim of
this proposal is to investigate Sema4D treatment as an acute, anti-seizure therapeutic in rodent
models of status epilepticus (SE). SE is a medical emergency requiring immediate intervention
in humans; approximately 30% of patients with SE are refractory to treatment with current
medications including benzodiazepines. Preliminary data presented in this proposal shows that
Sema4D treatment restored the efficacy of diazepam in a rodent model of refractory SE. This
result is consistent with our hypothesis that Sema4D treatment acutely increases the number of
GABAergic synapses in hippocampus, which maintains or re-establishes benzodiazepine
sensitivity in the brain.
 The second aim of our proposal is to determine the effect of chronic exposure of
Sema4D (via viral delivery to the CNS) on inhibitory synapse formation and ultimately, seizure
frequency and severity in rodent models of chronic epilepsy. As a first step towards this goal we
will explore the efficacy and time-course of alternative methods of administering Sema4D (e.g.
intracerebral injection of virus encoding Sema4D) to mice. In the third aim, we will begin to
address the translatability of our findings with Sema4D in rodents by asking if Sema4D
promotes inhibitory synapse formation and network activity in cultures of human neurons.

## Key facts

- **NIH application ID:** 10372126
- **Project number:** 5R01NS065856-11
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** SUZANNE PARADIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $571,226
- **Award type:** 5
- **Project period:** 2010-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372126

## Citation

> US National Institutes of Health, RePORTER application 10372126, Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain (5R01NS065856-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372126. Licensed CC0.

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