SUMMARY
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 my lab discovered that the secreted 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 the
extracellular domain of Sema4D into the adult hippocampus rapidly promotes the formation of new
GABAergic synapses. Importantly, these data demonstrate that the molecular machinery regulating
GABAergic synaptogenesis in the young hippocampus remains functional in the adult and that this machinery
can be harnessed to modulate network excitability. We directly addressed this point by demonstrating that
Sema4D treatment protects against seizures induced by direct electrical stimulation of the hippocampus or by
intravenous infusion of the proconvulsant drug pentylenetetrazol. Further, we found that Sema4D treatment
restored the efficacy of diazepam in a rodent model of refractory status epilepticus.
Given the success of these studies, my laboratory has undertaken a new experimental direction to determine if
Sema4D treatment has therapeutic potential for human epilepsies. We will focus our work on the translatability
of Sema4D as an anti-seizure therapeutic for treating status epilepticus (SE). Unfortunately, approximately
30% of patients with SE are refractory to treatment with current medications including benzodiazepines. One
hypothesis about the origin of refractoriness in status epilepticus is that prolonged neural depolarization leads
to internalization of cell-surface GABAA receptors, thus reducing total inhibitory current in response to
GABAergic signaling (Joshi & Kapur, 2012). We hypothesize that by acutely increasing the number of
inhibitory synapses using Sema4D treatment, we could maintain or re-establish benzodiazepine
sensitivity in the brains of these individuals. Second, in order to further our in vivo mouse studies of
Sema4D-dependent seizure suppression, and to further the translatability of our findings, we will explore
alternative methods of administering Sema4D (e.g. intravenous injection of virus encoding Sema4D) to mice.
Lastly, we will test the translatability of our findings with Sema4D in rodents by asking if Sema4D promotes
inhibitory synapse formation in human neurons.
