Neuroscience Student Earns Prestigious NIH Fellowship

By Dirk Hoffman

The $71,430 Ruth L. Kirschstein F31 National Research Service Award for Individual Predoctoral Students supports training for a promising researcher in a health-related area.

The title of Schwarz’s grant is “Mechanism of Altered Synaptic Signaling by Disease Related GRIN1 Variants.”

NMDA receptors play essential roles in excitatory neurotransmission, synaptic plasticity, nervous system development, and learning and memory. They are expressed all throughout the brain and spinal cord at all stages of development.

These receptors are composed of four subunits, one of them being the obligatory GluN1 subunit, which is encoded by the GRIN1 gene. The GRIN1 gene has several naturally occurring variations that can cause disease in patients because of NMDA receptor malfunction.

Schwarz says her research aims to functionally characterize disease-related variants in the GRIN1 gene, in order to get a better understanding of how NMDA receptors contribute to brain health and disease.

“I will also investigate pharmacological rescue of these variants in both cultured cells and in brain slices,” she says. “The methods I use involve electrophysiology, which allows me to study the electrical and synaptic activity of cells that express the disease-related mutations.”

Schwarz notes that many children suffer from GRIN1-related disorders (its prevalence is about 5.45 per every 100,000 births). They experience symptoms that include epileptic seizures, intellectual disabilities, and movement disorders.

“The drugs and activity modulators I test in the lab may hold great promise for these patients because they have shown to boost mutant receptor activity,” she says. “Though these drugs are still experimental and cannot be prescribed to patients yet, they offer us an encouraging first step in finding these children more viable treatment options.”

Schwarz works in the lab of Gabriela K. Popescu, PhD, professor of biochemistry, who says that F31s are highly regarded awards within the National Institutes of Health (NIH).

“Applications undergo a strict peer review process, and the funds are limited, leading to stiff competition,” she says. “Historically, success rates for NINDS F31s hover around 23%.”

Schwarz is the fifth student of Popescu’s to secure an “F series” award from the NIH.

“My dad used to say that ‘you cannot pass an exam for which you don’t show up,’” Popescu says. “Therefore, the first rule in my lab is that I expect all my trainees to prepare and submit an F-type application to the NIH.”

“This means that the project they propose, while related to the general questions we address in my lab, must be independent of research that NIH is already funding under my name. In other words, I challenge my trainees to be creative and to take ownership of a research question and a feasible approach.”

But Popescu stresses that this does not mean the students are on their own.

“I work actively with each of my trainees in developing their independent project to ensure that it inspires and motivates them, that it ignites their passion and curiosity,” she says.

Popescu says all Jacobs School students benefit from the counsel and advice of a dedicated group of faculty — their graduate committee.

“I credit in large part the success of my trainees to the high standards and expert guidance provided by my colleagues, who have generously given of their time and energy to serve on my students’ graduate committees over the years” she says. “I cannot be more grateful for their support.”

Popescu says it was a lucky coincidence that when Schwarz joined her lab to learn about NMDA receptors, a colleague at the University of Toronto had just developed a mouse line for the rare GRIN disorder identified in a handful of patients.

“Samantha is passionate about finding cures for people suffering from neuropsychiatric diseases,” she says. “She was inspired by the direct relevance of a project that would reveal the molecular cause of this disease. Her project aims to find what is different about NMDA receptors that have the exact mutation identified in patients, and how to restore it to a more normal function.”

Schwarz notes this was actually her second time submitting an F31 — her first application was “triaged,” or not given a score, which happens to about half of submitted applications.

“Because this was a resubmitted application, Dr. Popescu helped me with fully comprehending and addressing my reviewer comments to strengthen it,” she says. “When my first application was not scored, I felt a little disheartened, but Dr. Popescu encouraged me to apply again and to practice resilience, and looking back in hindsight, I’m very glad that I took her advice!”

Popescu says it is not uncommon for a very good application to be triaged.

“Samantha submitted her first application very early in her training and her reviewers were not convinced of the feasibility of the project,” she says.

In the meantime, with Popescu’s encouragement, Schwarz attended a prestigious training course at Cold Spring Harbor Laboratory and presented some of her preliminary data on the project at the Annual Meeting of the Biophysical Society.

“I believe these achievements convinced the reviewers that Samantha will overcome the inherent difficulties of the project she proposed, and in doing so she would gain valuable expertise and skill,” Popescu says.

“I encouraged and supported her to consider and address point-by-point all comments made by reviewers of her first application,” she adds. “And I encouraged and supported her to take the time to prepare a resubmission. You cannot pass the exam if you don’t show up, remember?”