Summary: Sema4D not only reduces the severity of seizures in mouse models of epilepsy, it also helps to increase the number of inhibitory synapses in the brains of the animals, researchers report.
Source: Brandeis University.
Researchers in the lab of Associate Professor of Biology Suzanne Paradis have discovered a novel treatment for reducing seizure activity in the brains of rodents, a discovery they hope might one day help people living with epilepsy.
An estimated 2.2 million Americans suffer from epilepsy and 20 to 30 percent of these individuals live with seizures that do not respond to current medications.
The research was published this spring in the journal Epilepsia. The first author was Daniel Acker, Ph.D. ’18, a former graduate student in Paradis’ lab now at Insight Data Science. The other authors were Irene Wong ’17 and Mihwa Kang.
Paradis’s lab researches synapses, the connections between brain cells. Most synapses are excitatory — they facilitate the passage of signals from one brain cell to another. Others though are inhibitory, thwarting transmission.
During an epileptic seizure, the balance between excitation and inhibition goes out of whack, favoring excitation. The result is a kind of power surge where excessive electrical activity causes uncontrolled convulsions, unconsciousness or a temporary loss of awareness.
Several years ago, Paradis and her collaborators pinpointed a protein, Semaphorin 4D (Sema4D), that stimulates production of inhibitory synapses. In brain tissue taken from mice, the researchers showed that bathing the cells in Semaphorin 4D increases the number of inhibitory synapses, ameliorating the hyperexcitability, or signal overload, associated with epileptic seizures. These changes happened surprisingly quickly, within minutes.
In the latest research, the Paradis group worked with mice with symptoms resembling those found in epileptic humans. They applied an infusion of Sema4D into the animals’ brains. The mice experienced a reduction in the severity of their seizures.
The scientists also observed an increase in the number of inhibitory synapses in the brains of these animals, leading them to conclude that Sema4D treatment increases the brain’s overall resistance to seizures by increasing the number of inhibitory synapses.
“Our idea is simple and has high impact potential,” Paradis said. “On command, we instruct neurons to assemble more inhibitory synapses in the brain, thus suppressing seizures. This approach could also be beneficial in preventing the establishment of epilepsy, halting its progression or suppressing hyperexcitability during a seizure event.”
In the future, if Sema4D treatment were to work in humans, Paradis envisions that Sema4D could be used in combination with current anti-epileptic drugs, such as benzodiazepines, that work by increasing the function of existing inhibitory synapses.
Paradis will focus next on finding a mechanism, perhaps a drug or gene therapy, to deliver Sema4D to the right target in the brain. Though it’s still unknown if the approach will succeed in humans, Acker said, “the excitement is that the general approach works.”
Source: Lawrence Goodman – Brandeis University
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Original Research: Abstract for “Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo” by Daniel W. M. Acker, Irene Wong, Mihwa Kang, and Suzanne Paradis in Epilepsia. Published May 25 2018.
Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo
We previously discovered a role for the extracellular domain of the transmembrane protein semaphorin 4D (Sema4D) as a fast‐acting, selective, and positive regulator of functional γ‐aminobutyric acid (GABA)ergic synapse formation in hippocampal neuronal culture. We also demonstrated that Sema4D treatment increases inhibitory tone and suppresses hyperexcitability in an organotypic hippocampal slice culture model of epilepsy. Here, we investigate the ability of Sema4D to promote GABAergic synapse formation and suppress seizure activity in vivo in adult mice.
We performed a 3‐hour, intrahippocampal infusion of Sema4D or control protein into the CA1 region of adult mice. To quantify GABAergic presynaptic bouton density, we performed immunohistochemistry on hippocampal tissue sections isolated from these animals using an antibody that specifically recognizes the glutamic acid decarboxylase isoform 65 protein (GAD65), which is localized to presynaptic GABAergic boutons. To assess seizure activity, we employed 2 in vivo mouse models of epilepsy, intravenous (iv) pentylenetetrazol (PTZ) and hippocampal electrical kindling, in the presence or absence of Sema4D treatment. We monitored seizure activity by behavioral observation or electroencephalography (EEG). To assay the persistence of the Sema4D effect, we monitored seizure activity and measured the density of GAD65‐positive presynaptic boutons 3 or 48 hours after Sema4D infusion.
Sema4D‐treated mice displayed an elevated density of GABAergic presynaptic boutons juxtaposed to hippocampal pyramidal neuron cell bodies, consistent with the hypothesis that Sema4D promotes the formation of new inhibitory synapses in vivo. In addition, Sema4D acutely suppressed seizures in both the PTZ and electrical kindling models. When we introduced a 48‐hour gap between Sema4D treatment and the seizure stimulus, seizure activity was indistinguishable from controls. Moreover, immunohistochemistry on brain sections or hippocampal slices isolated 3 hours, but not 48 hours, after Sema4D treatment displayed an increase in GABAergic bouton density, demonstrating temporal correlation between the effects of Sema4D on seizures and GABAergic synaptic components.
Our findings suggest a novel approach to treating acute seizures: harnessing synaptogenic molecules to enhance connectivity in the inhibitory network.