Seizures: Cause and Possible Prevention
Jamie Maguire, PhD, joined the Department of Neuroscience at Tufts University School of Medicine in 2010. She is a member of the graduate programs in Neuroscience and Pharmacology & Experimental Therapeutics of the Sackler School of Graduate Biomedical Sciences. Maguire earned her doctorate in neuroscience from George Washington University and did postdoctoral research at the University of California – Los Angeles. “My background is primarily in epilepsy research, and we’ve been focusing on the potential role of GABA [gamma aminobutyric acid] receptors,” says Maguire. Epilepsy is a neurological disorder characterized by seizures, which often manifest as convulsions or loss of consciousness. GABA is the primary inhibitory neurotransmitter in the adult nervous system; GABA works with other neurotransmitters and hormones to control neurological activity. Maguire and her research group are working to understand how changes in GABAergic inhibition can precipitate seizures, and what might be done to limit or prevent such seizures.
GABA is involved in the stress response, and stress can trigger seizures, so Maguire has begun to focus on how stress is involved in neurological disorders such as epilepsy. The “fight-or-flight” stress response of increased heart rate, blood pressure, and stress hormones is primarily controlled by corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus region of the brain. In December 2011, Maguire and her research group presented a hypothesis for how CRH neurons mount a stress response. GABA’s inhibitory effect on neurotransmission is well known to depend on the chloride gradient—the difference between the chloride concentration inside and outside the cell. The work of Maguire’s research group indicates that stress causes a transient collapse in the chloride gradient, changing GABA’s effect on neurotransmission from inhibitory to excitatory. Furthermore, the neurosteroid tetrahydrodeoxycorticosterone (THDOC) acts on the GABAA δ subunit–containing receptor of CRH neurons to activate them. “We think that the fastest way to overcome all the GABAergic inhibition is to transiently make GABA excitatory and activate these neurons to mount the stress response,” says Maguire. “We have fairly strong evidence that this occurs following an acute stress, and we’re now looking at whether this happens following chronic stress, or how different types of stressors alter this.”
Some GABA receptors are sensitive to derivatives of hormones, including stress hormones, and alterations in the expression of these receptors have been associated with depression. Maguire is trying to understand the mechanisms of GABA receptor regulation and figure out how receptors may be modulated to prevent or limit both seizures and depression. Current research involves mouse models of stress, epilepsy, and depression in studies of drugs that are known to affect specific GABA receptors and various regulators of the chloride gradient.
Another avenue of research in the Maguire lab involves investigating seizure generation in a mouse model of tumor-associated epilepsy. Seizures are associated with glioblastoma multiforme in both mice and humans, and in some instances seizures continue even after the tumor is removed. Maguire’s research group will be investigating how the tumor causes seizures in the mouse model. “We’re focusing on changes in GABAergic inhibition that are happening in the native tissue surrounding the tumor,” she says. “We’re trying to figure out what those changes are so that if the tumor is resected, we can at least find a target for seizure control in those patients.” The researchers, in collaboration with Julian Wu in the Department of Neurosurgery at Tufts Medical Center, will also be looking at glioblastoma multiforme tumor tissue that has been removed from patients to see if what they’re finding in the mouse model is also happening in humans. “We’re looking at patients who present with seizures versus patients who don’t present with seizures to figure out how they’re different,” she says.
Maguire enjoys collaboration and can offer researchers her lab’s expertise in slice electrophysiology in mouse models. She would like to find a collaborator interested in doing computer modeling of neural networks. “A lot of the things that we’re seeing could be explored using computer models, and we don’t do any computer modeling,” says Maguire. She would also like to collaborate with someone with expertise in testing for anesthetic sensitivity in mouse models. “The thalamus has a very high density of GABA receptors that we are investigating,” she says. “We have a feeling they might be involved in sleep or anesthesia, so we’d like to knock them out in that brain region and then test to see if they have any differences in anesthetic sensitivity.” A collaborator with expertise in a standardized test for anesthetic sensitivity in mice would help advance this direction of Maguire’s research.
For more information, please see The Jamie Maguire Lab.