Not all neurons shake during seizures

Sophie Liebergalls is a 7th MD-PhD student who is mentored by Ethan Goldberg at the Children's Hospital of Philadelphia. She is interested in how different types of neurons in the brain send signals to other neurons along their axons, and how this process may be impaired in diseases like epilepsy. After completing medical school, she plans to do a residency in Pediatric Neurology and try to bring insights from the lab to the care of children with neurologic diseases.

or technically,

Ndnf Interneuron Excitability Is Spared in a Mouse Model of Dravet Syndrome

[See Original Abstract on Pubmed]

Authors of the study: Sophie Liebergall, Ethan Goldberg.

Neurons, the cells in our brains, communicate with each other with electricity. Usually, the amount of electricity is carefully regulated, allowing neurons to pass signals to each other in a controlled way. However, sometimes there is a sudden burst of electricity in the brain, causing a seizure. Many people will experience a single seizure during their lifetime, but people with regular seizures are diagnosed with epilepsy. Epilepsy is a broad category of brain disease that affects up to 50 million people worldwide. Some types of epilepsy can be managed with medication, but others are treatment-resistant and very difficult to control.

Dravet syndrome is one example of a disorder that causes treatment-resistant epilepsy. It’s a rare neurodevelopmental disorder that causes severe, frequent seizures starting in the first year of life, plus intellectual disability and developmental delay. Scientists have figured out what causes this disorder: mutations in a single gene called SCN1A. SCN1A is a gene that contains the instructions to make Nav1.1, one of the brain’s sodium channels. Some types of neurons in the brain rely on Nav1.1 to generate and control their electrical signals. Even though we understand the cause, there is still no cure for Dravet syndrome, and there is no current treatment that can fully manage patients’ symptoms. Scientists are still working to better understand the effects of mutations in SCN1A in neurons, with the hopes that new knowledge could eventually lead to new treatment strategies.

There are many different types of neurons in the brain, and scientists have learned that the gene SCN1A is most highly expressed in a group of neurons called inhibitory neurons. These neurons work by quieting their neighbors, helping to prevent runaway activity in the brain. Because SCN1A is especially important for these inhibitory neurons, scientists think that mutations in this gene disrupt the brain’s electrical balance: when inhibitory neurons can’t do their job, their neighbors can become overactive, leading to seizures.

Sophie Liebergall, a current NGG student, wanted to learn more about whether all inhibitory neurons are affected by SCN1A mutations. Specifically, she looked at a group of inhibitory neurons that express a protein called Ndnf. SCN1A mutations, like those that cause Dravet syndrome, impair the ability of some types of inhibitory neurons to generate electrical signals, but we didn’t know anything about what happens to Ndnf inhibitory neurons. The goal of Sophie’s study was to see whether Ndnf inhibitory neurons are disrupted similarly to other inhibitory neurons when there are errors in the SCN1A gene.

To investigate this question, Sophie used a mouse model of Dravet syndrome, where one of the two copies of Scn1a was genetically removed from all neurons. She then measured the electrical properties and activity of Ndnf inhibitory neurons in these mice, and she compared their properties to Ndnf interneurons in healthy mice with both working copies of Scn1a.

Surprisingly, Sophie found that Ndnf inhibitory neurons seemed totally unaffected by the missing copy of Scn1a -- their electrical properties were similar to those of healthy neurons. This was unexpected because the electrical properties of other types of inhibitory neurons are really different when they’re missing a copy of Scn1a. Sophie also found that these neurons do not seem to depend on the protein encoded by Scn1a to generate their electrical signals, which may explain why their activity was normal.

Sophie’s findings are important because they challenge the simple version of the hypothesis that seizures in Dravet syndrome are caused by a blanket loss of inhibitory neuron function. Instead, Sophie’s study shows that the story is more complex: some inhibitory neurons, like Ndnf neurons, remain fully functional even when Scn1a is missing. These results reshape our understanding of the disease mechanisms of Dravet syndrome and open the door to more targeted approaches in treating the disorder. More broadly, Sophie’s work reminds us to pay attention to the full diversity of neurons. The brain is complex, and it is only by appreciating and dissecting this complexity that we will be able to understand how the brain works and how it goes wrong.

Great work Sophie!

About the brief writer: Lyndsay Hastings

Lyndsay Hastings is a PhD candidate in NGG working in Dr. Tim Machado’s lab. She is interested in how the brain generates flexible and complex movement.

Curious about Sophie’s research? Check out the full paper here!