June 2, 2014

CURE Conversations: Janice R. Naegele, PhD

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
I am a Professor of Biology, Neuroscience and Behavior at Wesleyan University, where I have been on the faculty for 23 years. In addition to teaching courses in neuroscience and developmental neurobiology, I especially enjoy working closely with students in my research laboratory. My research group includes undergraduates, Masters, and PhD students, and my lab manager/research technician. In addition to research and teaching, I direct the Wesleyan Center for Faculty Career Development. As part of this job, I mentor and help to train junior faculty and have a strong commitment to promoting inclusion of women and minorities in science and mathematics. I am also involved in advocacy work on behalf of the American Epilepsy Society, and I serve on the Board of Trustees of the Lennox-Lombroso Trust.

What motivated you to become interested in this area of research?
I have a long-standing interest in neuronal regeneration and neural plasticity. My lab has worked for many years on GABAergic interneurons and their roles in neural development and epilepsy. Our research focusing on stem cell therapies for temporal lobe epilepsy developed as a result of conversations with clinicians working with patients with severe intractable seizures and scientific discussions with stem cell biologists. My father-in-law, the late Dr. Cesare Lombroso, had a tremendous impact on my decision to shift my laboratory’s research focus from neural development to translational models of epilepsy and the development of therapies.

What is your current research focus?
In my lab, we are broadly interested in understanding the mechanisms of epileptogenesis and in developing stem cell transplantation approaches for stimulating repair of hippocampal circuits in mouse model of temporal lobe epilepsy. A sustained seizure may trigger GABAergic interneuron cell death in the hippocampus and related limbic circuits, and increase the rate of adult granule cell neurogenesis, axonal sprouting and other plastic changes.

These neuroplastic changes contribute to hyperexcitability, spontaneous seizures, and can lead to cognitive impairments. Our research focuses on preventing the degeneration of GABAergic interneurons after seizures and on developing cell-based therapies to replace these neurons to cure temporal lobe epilepsy. We are testing the ability of mouse and human embryonic stem cell-derived GABAergic neurons and fetal GABAergic cells to integrate and form synapses with adult-born granule neurons after the stem cells are transplanted into the hippocampus of adult mice with TLE.

Our studies monitoring seizures behaviorally and with electroencephalography have shown that GABAergic progenitors suppress seizures and integrate into mature hippocampal neural circuits. We are studying how the transplanted neural stem cells integrate synaptically and whether they improve disease outcomes.

Can you share some of the latest findings?
In rodent epilepsy models, transplants of a certain cell type that inhibit brain activity provide short-term seizure suppression. Few studies have examined the cellular mechanisms or the long-term effects of these transplants on seizure suppression. In this study, we examined seizure frequency and duration for over 100 days following cell transplant. Compared with controls, mice with temporal lobe epilepsy that had transplants showed significant attenuation of spontaneous seizures, beginning by about 3-4 weeks after transplantation.

To determine whether the gradual disease modifying effects of the transplants were due to increased inhibition of a certain type of cell, we measured several physiological properties of the cells. Our data suggest that greater inhibition is responsible for attenuating spontaneous seizures. Furthermore, strong seizure suppression was associated with the formation of new inhibitory networks in certain areas of the brain near the transplant. These results indicate that transplanted inhibitory cells mediate long-term spontaneous seizure suppression by forming new inhibitory networks with the hyperexcitable cells thought to contribute to seizure generation.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
The goal of our research is to develop and optimize cell-based therapies for treating patients with severe temporal lobe epilepsy and other forms of intractable seizures. Before moving into the clinic, it is essential that we understand the mechanisms for integration of transplanted cells, whether these transplanted cells can survive for long periods, how they wire up with cells in the host brain, and whether they have adverse consequences or beneficial effects on cognition, in addition to suppressing seizures.

What accomplishment—personal or professional—are you most proud of?
I am extremely proud of my former trainees and students, many of whom have gone on to careers in basic neuroscience research or clinical medicine. Many of them are currently working in basic neuroscience research or exploring frontiers in translational neuroscience to understand the causes of epilepsy and other neurological conditions.