Intractable epilepsy remains a significant problem, and mesial temporal lobe epilepsy (MTLE), also known as chronic limbic epilepsy (CLE), is a common epilepsy syndrome that is frequently intractable. Although much is known about several regions of the brain that are associated with various stages of the seizures, little is known about the specific roles these particular regions play in the initiation of seizures, or how they interact with the other likely components of the seizure circuits. Knowing this information is essential for understanding the pathophysiology of limbic epilepsy and for targeting therapy. To examine this issue, seizures have to be studied in intact systems. In this project we propose to evaluate the roles of several candidate circuits and regions in the initiation and generalization of limbic seizures: the trisynaptic hippocampal-entorhinal loop and the medial dorsal thalamic nucleus-limbic circuits. Specifically we will test the hypotheses that one or both are key elements in the initiation of the seizures and the spread of seizures to other parts of the brain. We will also examine whether it is possible to modulate seizures by stimulation of afferents to these sites. At the end of the project we will have identified key control points in the evolution of limbic seizures and possible ways to use these points for improved therapies.

Public Health Relevance

In this application we are proposing to examine the network interactions that underlie seizure initiation and generalization in limbic epilepsy. Although the brain regions that are involved in seizures are well known, how the different parts get involved and how they interact with one another is not well understood. This information is essential for the identification of targets for therapy and for directing future research to the key elements of the seizure circuits. We will use several in vivo seizure models, including a model with spontaneous limbic seizures to tease out the various components of each seizure stage in an intact nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Whittemore, Vicky R
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University of Virginia
Schools of Medicine
United States
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Bertram, Edward H (2013) Neuronal circuits in epilepsy: do they matter? Exp Neurol 244:67-74
Sloan, David M; Zhang, Dexing; Bertram 3rd, Edward H (2011) Excitatory amplification through divergent-convergent circuits: the role of the midline thalamus in limbic seizures. Neurobiol Dis 43:435-45
Sloan, David M; Zhang, DeXing; Bertram 3rd, Edward H (2011) Increased GABAergic inhibition in the midline thalamus affects signaling and seizure spread in the hippocampus-prefrontal cortex pathway. Epilepsia 52:523-30
Thom, Maria; Mathern, Gary W; Cross, J Helen et al. (2010) Mesial temporal lobe epilepsy: How do we improve surgical outcome? Ann Neurol 68:424-34
Sloan, David M; Bertram 3rd, Edward H (2009) Changes in midline thalamic recruiting responses in the prefrontal cortex of the rat during the development of chronic limbic seizures. Epilepsia 50:556-65
Bertram, Edward H (2009) Temporal lobe epilepsy: where do the seizures really begin? Epilepsy Behav 14 Suppl 1:32-7
Rajasekaran, Karthik; Sun, Chengsan; Bertram, Edward H (2009) Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy. Neurobiol Dis 33:119-32
Bertram, Edward H; Zhang, DeXing; Williamson, John M (2008) Multiple roles of midline dorsal thalamic nuclei in induction and spread of limbic seizures. Epilepsia 49:256-68
Sun, Chengsan; Mtchedlishvili, Zakaria; Bertram, Edward H et al. (2007) Selective loss of dentate hilar interneurons contributes to reduced synaptic inhibition of granule cells in an electrical stimulation-based animal model of temporal lobe epilepsy. J Comp Neurol 500:876-93
Rajasekaran, Karthik; Kapur, Jaideep; Bertram, Edward H (2007) Alterations in GABA(A) receptor mediated inhibition in adjacent dorsal midline thalamic nuclei in a rat model of chronic limbic epilepsy. J Neurophysiol 98:2501-8

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