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Future Stem Cell-based Therapies for Treating Epilepsy Explored in 3 Biology Labs

Janice Naegele, professor of biology, professor of neuroscience and behavior, and her lab manager, Stephanie Tagliatela, review the brain activity of four mice that are currently being treated for epilepsy using therapies developed and tested in the lab. (Photos by Olivia Drake)

For the roughly one-third of temporal lobe epilepsy patients for whom drugs are not an option, researchers at Wesleyan are paving the way for alternative therapies using stem cells.

Biology Department faculty members Gloster Aaron, Janice Naegele and Laura Grabel work together to create novel cell replacement therapies for temporal lobe epilepsy.

Faculty members Janice Naegele, Gloster Aaron and Laura Grabel, together with Xu Maisano, Ph.D. ’11, Elizabeth Litvina, B.A. ’10/M.A. ’11, and Stephanie Tagliatela, the lab manager in the Naegele lab, recently published a landmark study in the Journal of Neuroscience on the use of embryonic stem cells to treat temporal lobe epilepsy (TLE). The researchers derived neural “parent cells” in culture from mouse embryonic stem cells, and transplanted them into the brains of epileptic mice. There, the transplanted cells differentiated into mature inhibitory neurons and successfully integrated and formed connections in the host brain over the course of several months.

The paper, published Jan. 4, is available to read online.

“In these experiments, we are attempting to repair an important region called the dentate gyrus, located deep inside the temporal lobe in the hippocampus. The structures affected in temporal lobe epilepsy are important for forming memories and controlling the spread of seizures throughout the brain. When inhibitory neurons in the hippocampus are injured or die off, seizures are able to spread into other brain regions, causing more severe seizures,” explains Naegele, professor of biology, professor of neuroscience and behavior.

Naegele, Aaron, Grabel, Xu ’11, Litvina ’11 Published in Journal of Neuroscience

An article written by three Wesleyan faculty and two alumni was published in the January 2012 issue of the Journal of Neuroscience, 32(1): pages 46-61.

In “Differentiation and functional incorporation of embryonic stem cell derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy,” the authors describe embryonic stem cell derived neuronal transplants for treating temporal lobe epilepsy.

The authors include Jan Naegele, professor of biology, professor of neuroscience and behavior; Gloster Aaron, assistant professor of biology, assistant professor of neuroscience; Laura Grabel, the Lauren B. Dachs Professor of Science and Society, professor of biology;  Xu Maisano Ph.D. ’11; and Elizabeth Litvina B.A./M.A. ’11. Xu was the lead author. This study is part of a larger effort between three biology labs (Naegele, Aaron, and Grabel) to study embryonic stem cell therapies for temporal lobe epilepsy.

In this large, multi-year study, the authors show that embryonic stem cell derived neurons can develop into the major type in inhibitory neuron that degenerates in severe temporal lobe epilepsy. Because these interneurons reside in a part of the hippocampus that controls the spread of seizures throughout the cortex, when these neurons are injured or die off, seizures are able to spread throughout the hippocampus and into other brain regions, causing a more severe seizure.

“We believe that these findings are of high importance for developing stem cell based treatments for brain repair and regeneration,” Naegele explains.

 

Vallo ’13 Studies Seizure Suppression, Teaches Local Students about Science

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This summer, Mary Vallo '13 developed a needs assessment for the Epilepsy Foundation of Connecticut. She also volunteers in the Wesleyan Science Outreach club and plays intramural soccer. (Photo by Bill Tyner '13)

Q: Mary, what is your class year, and what are you majoring in?

A: I’m a junior, and I’m double-majoring in neuroscience and behavior and English.

Q: You’re currently working in the lab of Jan Naegele, professor of neuroscience and behavior, professor of biology. Can you tell us a bit about your research in the Naegele Lab?

A: The Naegele Lab studies temporal lobe epilepsy (TLE), which involves instances of elevated electrical activity in the brain called seizures. In cases where medication does not alleviate seizures, TLE patients experience cell death and damage in the dentate gyrus, part of the hippocampal region of the brain. Using a mouse model of TLE, our goal is to replenish the damaged neurons via stem cell injections. And since seizure-related cell death especially affects a type of interneuron that normally inhibits electrical impulses, we hope that restoring those interneurons will help to suppress seizure activity.

Q: This summer, you participated in the Wesleyan University Hughes Program, funded by the Howard Hughes Medical Institute. What was your summer-long research project?

A: The project that I began over the summer analyzes brain sections from epileptic mice that have received stem cell transplants. I stain for a protein that marks transplanted cell axons and another protein called gephyrin that is found at inhibitory synapses. So far, I have found several instances where transplant axons overlap with gephyrin. These findings suggest that the stem cells form inhibitory connections that may contribute to seizure suppression.

Grabel Receives New Human Stem Cell Research Grant

Laura Grabel

Professor Laura Grabel has received a $750,000 grant from The State of Connecticut Stem Cell Research Advisory Committee for her study titled “Angiogenesis of Embryonic Stem Cell Derived Hippocampus Transplants.” It is her third grant from the Committee since Connecticut began its state-funded human stem cell research program in 2006, and second where she is the principal investigator (P.I); she was co-P.I. on the other.

Grabel, professor of biology and Lauren B. Dachs Professor of Science in Society, is also a co-director of Connecticut’s Human Embryonic Core Facility, a research center in Farmington, Conn. that houses some human stem cell research performed by scientists from Wesleyan, The University of Connecticut, and The University of Connecticut Health Center.

The new grant will fund a study that builds on previous research

Neuroscience and Behavior Capstone Focuses on Service

Mandela Kazi ’12 speaks about "The Human Connectome Project." Plastic model brains are arrayed on the table in front of him.(Photo by David Pesci)

“Let’s pass around the brains, but please be careful,” Jennifer Cheng ’11 says. “They break easily.”

Maryann Platt ’11 and Mandela Kazi ’12 hand out the brains, detailed plastic models with interlocking, removable pieces that allow anyone picking them up to study the organ’s specific areas.

“I don’t think you need to use the stands,” says Janice Naegele, professor of biology, professor of neuroscience and behavior.  “I think you can just give them the brains.”

The students nod and make a note and return to their presentation, titled “The Human Connectome Project,” which focuses on the brain, connectomes and the new 3-D technology being used to better map both. The presentation is a practice session that the other students in the class, Neuroscience and Behavior (NS&B) 360, watch and then give feedback. The real thing came a few weeks later in front of high school students, an event that the NS&B 360 students have been anticipating all semester.

NS&B 360 is a new offering this year, a combination capstone course – an intense, rigorous experience that is cumulative and requires students to draw on their previous coursework – as well as a service-learning course, which combines active learning with providing a service to the local community.

Naegele Published in Epilepsy Publications

Jan Naegele, professor of biology, professor of neuroscience and behavior, is the author of “Tangled Roots: Digging Deeper into Astrocyte or Interneuron Dysfunction in Temporal Lobe Epilepsy,” published in Epilepsy Currents, Volume 11, Issue 1, 2011. The article is online here.

She’s also the author of “STEP Regulation of Seizure Thresholds in the Hippocampus,” published in Epilepsia by Wiley Publishers, 2011. The article is online here.

Aaron, Naegele, Briggs, Walker, Asik Published in Epilepsia Journal


The March 2011 cover of Epilepsia.


Faculty, alumni and students from the Biology Department and Neuroscience and Behavior Department have an article titled “STEP regulation of seizure thresholds in the hippocampus,” published in Epilepsia, Volume 52, Issue 3, March 2011. Epilepsia is the journal of the International League Against Epilepsy.

The paper’s co-authors include Gloster Aaron assistant professor of biology, assistant professor of neuroscience and behavior; Janice Naegele, professor of biology, professor of neuroscience and behavior; Stephen Briggs BA ’07, MA ’08, Jeffrey Walker BA ’08, MA ’09, and biology Ph.D. candidate Kemal Asik. Paul Lombroso, a professor at Yale University, contributed to the report.

This study found that mice lacking a specific enzyme (STEP) have a significantly heightened resistance to developing epileptic seizures. The study then documents a mechanism and location in the brain where this enzyme might have its effect in regulating the seizure thresholds. Briggs and Walker were BA/MA students in the NS&B program, and they worked in the labs of Naegele and Aaron, respectively. Asik works with John Kirn, chair of the Neuroscience and Behavior Department.

Naegele, Students Attend “Mysterious Brain” Forum

Janice Naegele, professor of biology, professor of neurosceince and behavior, and a group of Wesleyan students attended the Connecticut Forum on “The Glorius, Mysterious Brain” Feb. 25 at the Bushnell Theater in Hartford, Conn. The Connecticut Forum is a nationally recognized, nonprofit organization that offers live, unscripted panel discussions among renowned experts and celebrities, and community outreach programs. Nagele’s group listened to Autism advocate Temple Grandin, author and Harvard professor Steven Pinker and cognitive scientist Paul Bloom.

In addition, Michael Greenberg ’76, chair of neurobiology at Harvard Medical School, spoke to Naegele’s students about “experience-dependent changes in gene expression.”

Hingorani, Bricca Explain Science Documentary Filmmaking Class in ASBMB Today

Stephen Devoto, associate professor of biology, associate professor of neuroscience and behavior, is featured in a video created by a student enrolled in the course, Making the Science Documentary.

Manju Hingorani, associate professor of molecular biology and biochemistry, and Jacob Bricca, adjunct assistant professor of film studies, explained their experimental cross-disciplinary course on science documentary filmmaking at Wesleyan in a December 2010 article published in American Society for Biochemistry and Molecular Biology (ASBMB) Today.

In the article, Hingorani and Bricca wrote about their course, “Making the Science Documentary,” which they co-taught together, starting in 2007. The course was designed to introduce undergraduate students to the life sciences and to documentary filmmaking