Abstract
In the United States, epilepsy is the 4th most common neurological problem, as 1 in 26 people will develop this seizure disorder in their lifetime. A prominent theory supposes that many of these patients exhibit an excitation-inhibition (E-I) imbalance in the brain that is skewed towards excitation. We propose that increasing inhibitory synapse density can mitigate the hyperactivity seen in epilepsy. Semaphorin 4D (Sema4D) is a transmembrane protein that is necessary for proper inhibitory synapse development in hippocampal neurons, therefore we hypothesize that it may have utility as a novel antiepileptic drug. Our lab previously showed that the addition of Sema4D to primary rodent neuronal cultures promotes the rapid assembly of new inhibitory synapses. To investigate the effects of Sema4D in a more intact environment, we treated organotypic hippocampal slices with Sema4D. After a 2-hour treatment, Sema4D rapidly induced a transient increase in inhibitory synaptic markers. Additionally, Sema4D infusion into the in vivo hippocampus causes an increase in GAD65 puncta density when analyzed by immunohistochemistry. Our results suggest that Sema4D treatment promotes the formation of inhibitory synapses in vitro and in vivo and point towards possible therapeutic applications for E-I disorders.