Preclinical study sheds light on origin of epileptic seizures

New evidence from the zebrafish epilepsy model may help resolve the debate about how seizures arise, according to Weill Cornell Medicine and New York-Presbyterian investigators. The findings may also be useful in the discovery and development of epilepsy drugs in the future.

In the study, published February 23 in Brain, researchers were able to track the activities of neurons in all zebrafish larval brains during seizures. They show that seizures arise from increased activity of ‘excitatory’ over ‘inhibitory’ brain cells in relatively confined areas of the brain and spread only when they overcome strong inhibitory activity in surrounding areas.

Neurons in the brain come into two broad categories: excitatory neurons whose activity stimulates the activity of other neurons, and inhibitory neurons whose activity calms other neurons. Some recent studies have suggested that mutations in the activity of inhibitory neurons can paradoxically trigger seizures. The new results indicate otherwise.

“What’s really cool about the zebrafish model is that we can image every region of the brain, and in this model, for the first time, we’ve been able to characterize and track the activity of both excitatory and inhibitory neurons,” said first author James Niemeyer, a postdoctoral fellow at Neurosurgery at Weill Cornell Medicine. “So this is a good starting point for examining the exact roles of these cell types during seizures.”

Niemeyer is a member of the lab of co-lead author Dr. Theodore Schwartz, who is the David and Urcel Barnes Professor of Minimally Invasive Neurosurgery and Vice President of Clinical Research at Weill Cornell Brain and Spine Center at Weill Cornell Medicine and a neurosurgeon at NewYork-Presbyterian/Weill Cornell Center medical. Other co-authors on the study are Hongtao Ma, associate professor of neuroscience research in neurosurgery, and Emre Aksai, associate professor of physiology and biophysics, both at Weill Cornell Medicine.

Epilepsy is common, affecting approximately 50 million people worldwide at one time. But how it arose was not entirely clear. On the other hand, there is evidence that seizures arise from regions of the brain that favor the activity of excitatory neurons over the usual restraining effect of inhibitory neurons. On the other hand, several recent studies have suggested that excessive activity in inhibitory neurons may trigger seizures—and some researchers have observed early seizure activity in these cells. This has left a gap in understanding the different roles of excitation and inhibition in seizures.

Schwartz, who is also a professor of neurosurgery and neuroscience at Weill Cornell Medicine, said.

By using zebrafish, researchers have been able to overcome those challenges. Using special fluorescent probes, electrical recordings and a technique called two-photon microscopy, they simultaneously distinguished and tracked the activity of excitatory and inhibitory neurons across the brain, before and during seizures triggered by a standard chemical method.

They note that seizures in this model tend to originate in the midbrain, at sites with significant impairments in excitatory neural activity. The surrounding regions were more likely toward inhibitory activity, and for this reason were evidently able to resist, at least for a brief period, the spread of seizure activity from the initiation region.

The researchers suggested that previous studies that referred to inhibitory neurons as triggers of seizures may in some cases have only detected these highly inhibitory proliferation regions rather than the initiation region.

Aksai, who is also an associate professor of computational neuroscience in computational biomedicine at the HRH Prince Alwaleed bin Talal bin Abdulaziz Al Saud Institute for Computational Biomedicine at Weill Cornell Medicine.

The team plans to use the zebrafish model to screen for epilepsy drugs and hopes to confirm its findings in future experiments looking across multiple brain regions in a mouse model.

The research was funded in part by a Weill Cornell Medicine seed grant for interdisciplinary research that includes the Clinical and Basic Sciences departments.

Many physicians and scientists at Weill Cornell Medicine maintain relationships and collaborate with outside organizations to advance scientific innovation and provide expert guidance. The Foundation publishes these disclosures publicly to ensure transparency. For this information, see the profile of Dr. Theodore Schwartz.

Jim Schnabel is a freelance writer at Weill Cornell Medicine.

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