Janice Naegele and Laura Grabel will study if stem cell-based treatment in
mice brains could possibly control epileptic seizures in human brains.
Grant to Fund Epileptic Seizure Study at Wesleyan
A $300,000 grant from the McKnight Foundation
will help a Wesleyan University researcher investigate the possibility of
using brain transplants of embryonic stem (ES) cells to control epileptic
seizures in mice. If successful the study could lay the early groundwork for
using similar therapy in human beings.
Janice Naegele, chair and professor of biology and professor of neuroscience
and behavior at Wesleyan, is the principle investigator in the study that
will bring together the expertise two other Wesleyan faculty – Laura Grabel,
Fisk Professor of Natural Science, professor of biology, and Gloster Aaron,
assistant professor of biology – as well as Gordon Fishell, professor of
biology at New York University.
During the three-year study, Naegele and her colleagues will attempt to
create GABAergic neurons from mouse ES cells and implant them in the brains
of mice that experience epileptic seizures. The hope is that the new neurons
derived from the grafted ES cells will be able to restore normal levels of
the brain’s inhibitory neurotransmitter GABA by replacing GABAergic neurons
destroyed by the epileptic seizures. GABA is one of the key chemical
messengers in the brain that regulates the firing of neurons and prevents
“A lot of the focus in stem cell-based treatment is in treating
neurodegenerative disorders,” Naegele says. “Due to ethical roadblocks in
harvesting neural stem cells from human embryos, a preferred course is
autologous donation – taking an individual’s own stem cells and using them
to generate neural stem cells for treatment. However, in the case of some
forms of inherited epilepsy, there a genetic defect in the neurons that
causes the seizures. This defect is likely mirrored in the patient’s stem
cells, which is one reason why we are focusing on using non-autologous cell
From a clinical perspective, animal epilepsy isn’t identical in all facets
to human epilepsy. However, it is close enough that Naegele’s successful use
of these GABAergic neurons to control seizures will go a long way to help
scientists understand the potential treatment implications in humans.
For the study, the researchers will chemically induce the initial epileptic
seizures in the mice. After two to three weeks, the mice develop spontaneous
seizures, making the overall effect more similar to the way seizures occur
in humans. The stem cell grafts will be made into the brains of transgenic
mice that have fluorescent neurons, allowing the scientists to identify
interactions between the cells in the grafts and the host brains using a
combination of electrical recording and microscopic imaging. The studies
will attempt to demonstrate that the grafted stem cells form connections
with the host brain, a critical step for functional recovery from epilepsy.
To create the cells needed to potentially suppress the seizures, Naegele’s
team will use a new method to produce high yield GABAergic neurons.
“We plan to use molecular-genetic approaches to get the neural stem cells to
express a sequence of transcription factors that will regulate the genes
required to produce the GABAergic neurons,” Naegele says. “They will then be
transplanted to the mouse hippocampus and then we’ll see if they have enough
genetic information to act properly.”
Along with the faculty mentioned, this three-year study will also involve
post-doctoral students, graduate, and undergraduate students at Wesleyan who
will be assisting with components of the research.
“This is really exciting because it is bringing together three labs here and
a lab down at NYU,” Naegele says. “The expertise at each complements the
others. It’s a more risky study than others in this area, but the potential
information we can generate will really be useful as we move forward
investigating if this can be an effective treatment for epileptic seizures.”
In addition to supporting this collaboration, Naegele will participate in a
yearly McKnight Conference on Neuroscience, which fosters interactions among
the awardees of all of their programs. This year’s conference will be held
in the June 2007 in Aspen, Colorado and will focus on music, art, and the
According to their Web site, The McKnight Endowment Fund for Neuroscience is
an independent charitable organization established by The McKnight
Foundation to carry out the wishes of its founder, William L. McKnight
(1887-1979), who led the 3M company for three decades. McKnight had a
personal interest in memory and its diseases. He chose to set aside part of
his legacy to bring hope to those suffering from brain injury or disease and
cognitive impairment. The Neuroscience of Brain Disorders Awards were
established in 2000 as the Memory and Brain Disorders Awards. Each year, up
to six awards are given. Awards provide $100,000 per year for three years.
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By David Pesci, director of Media Relations.
Photo by Olivia Bartlett, The Wesleyan Connection editor