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The Journal of Neuroscience, April 26, 2006, 26(17):4613-4623; doi:10.1523/JNEUROSCI.0064-06.2006

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Neurobiology of Disease
Hyperexcitability, Interneurons, and Loss of GABAergic Synapses in Entorhinal Cortex in a Model of Temporal Lobe Epilepsy

Sanjay S. Kumar¹ and Paul S. Buckmaster^1,2

¹Departments of Comparative Medicine and ²Neurology and Neurological Sciences, Stanford University, Stanford, California 94305

Correspondence should be addressed to Paul Buckmaster, Department of Comparative Medicine, Stanford University, 300 Pasteur Drive, R321 Edwards Building, Stanford, CA 94305-5342. Email: psb{at}stanford.edu

Temporal lobe epilepsy is the most common type of epilepsy in adults, and its pathophysiology remains unclear. Layer II stellate cells of the entorhinal cortex, which are hyperexcitable in animal models of temporal lobe epilepsy, provide the predominant synaptic input to the hippocampal dentate gyrus. Previous studies have ascribed the hyperexcitability of layer II stellate cells to GABAergic interneurons becoming "dormant" after disconnection from their excitatory synaptic inputs, which has been reported to occur during preferential loss of layer III pyramidal cells. We used whole-cell recording from slices of entorhinal cortex in pilocarpine-treated epileptic rats to test the dormant interneuron hypothesis. Hyperexcitability appeared as multiple action potentials and prolonged depolarizations evoked in layer II stellate cells of epileptic rats but not controls. However, blockade of glutamatergic synaptic transmission caused similar percentage reductions in the frequency of spontaneous IPSCs in layer II stellate cells of control and epileptic rats, suggesting similar levels of excitatory synaptic input to GABAergic interneurons. Direct recordings and biocytin labeling revealed two major types of interneurons in layer III whose excitatory synaptic drive in epileptic animals was undiminished. Interneurons in layer III did not appear to be dormant; therefore, we tested whether loss of GABAergic synapses might underlie hyperexcitability of layer II stellate cells. Stereological evidence of fewer GABAergic interneurons, fewer gephyrin-immunoreactive punctae, and reduced frequency of spontaneous IPSCs and miniature IPSCs (recorded in tetrodotoxin) confirmed that layer II stellate cell hyperexcitability is attributable, at least in part, to reduced inhibitory synaptic input.

Key words: entorhinal cortex; temporal lobe epilepsy; interneurons; electrophysiology; anatomy; stellate cells

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Received Aug. 4, 2005; revised March 13, 2006; accepted March 16, 2006.

Correspondence should be addressed to Paul Buckmaster, Department of Comparative Medicine, Stanford University, 300 Pasteur Drive, R321 Edwards Building, Stanford, CA 94305-5342. Email: psb{at}stanford.edu

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