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The Journal of Neuroscience, November 15, 2006, 26(46):11850-11856; doi:10.1523/JNEUROSCI.2354-06.2006

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Neurobiology of Disease
Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

Chyze W. Ang,^1,2 * Gregory C. Carlson,^2 * and Douglas A. Coulter^1,2,3

¹Department of Bioengineering, University of Pennsylvania, ²Division of Neurology, Children's Hospital of Philadelphia, and ³Departments of Pediatrics, Neurology and Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Douglas A. Coulter, Abramson Pediatrics Research Center, Room 410, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

Epilepsy affects 1–2% of the population, with temporal lobe epilepsy (TLE) the most common variant in adults. Clinical and experimental studies have demonstrated hippocampal involvement in the seizures underlying TLE. However, identification of specific functional deficits in hippocampal circuits associated with possible roles in seizure generation remains controversial. Significant attention has focused on anatomic and cellular alterations in the dentate gyrus. The dentate gyrus is a primary gateway regulating cortical input to the hippocampus and, thus, a possible contributor to the aberrant cortical-hippocampal interactions underlying the seizures of TLE. Alternate cortical pathways innervating the hippocampus might also contribute to seizure initiation. Despite this potential importance in TLE, these pathways have received little study. Using simultaneous voltage-sensitive dye imaging and patch-clamp recordings in slices from animals with epilepsy, we assessed the relative degree of synaptic excitation activated by multiple cortical inputs to the hippocampus. Surprisingly, dentate gyrus-mediated regulation of the relay of cortical input to the hippocampus is unchanged in epileptic animals, and input via the Schaffer collaterals is actually decreased despite reduction in Schaffer-evoked inhibition. In contrast, a normally weak direct cortical input to area CA1 of hippocampus, the temporoammonic pathway, exhibits a TLE-associated transformation from a spatially restricted, highly regulated pathway to an excitatory projection with >10-fold increased effectiveness. This dysregulated temporoammonic pathway is critically positioned to mediate generation and/or propagation of seizure activity in the hippocampus.

Key words: dentate gyrus; entorhinal; hippocampus; inhibition; temporal lobe epilepsy; temporoammonic; voltage-sensitive dye imaging

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Received June 2, 2006; revised Sept. 29, 2006; accepted Sept. 29, 2006.

Correspondence should be addressed to Dr. Douglas A. Coulter, Abramson Pediatrics Research Center, Room 410, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

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