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The Journal of Neuroscience, November 14, 2007, 27(46):12641-12650; doi:10.1523/JNEUROSCI.4141-07.2007

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Neurobiology of Disease
Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the 4 Subunit of GABA_A Receptors in an Animal Model of Epilepsy

Chengsan Sun,^1 * Zakaria Mtchedlishvili,^1 * Alev Erisir,² and Jaideep Kapur¹

¹Department of Neurology, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908, and ²Department of Psychology, University of Virginia, Charlottesville, Virginia 22904

Correspondence should be addressed to Dr. Jaideep Kapur, Department of Neurology, Box 800394, Health Sciences Center, University of Virginia, Charlottesville, VA 22908. Email: jk8t{at}virginia.edu

In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA_A receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA_A receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the 4 subunit. Expression of the 4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the 4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The 4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and 4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.

Key words: GABA_A receptor 4 subunit; temporal lobe epilepsy; synapse; hippocampus; dentate granule cells; mIPSCs

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Received Jan. 29, 2007; accepted Oct. 2, 2007.

Correspondence should be addressed to Dr. Jaideep Kapur, Department of Neurology, Box 800394, Health Sciences Center, University of Virginia, Charlottesville, VA 22908. Email: jk8t{at}virginia.edu

This article has been cited by other articles:

				H.-J. Feng, G. C. Mathews, C. Kao, and R. L. Macdonald Alterations of GABAA-Receptor Function and Allosteric Modulation During Development of Status Epilepticus J Neurophysiol, March 1, 2008; 99(3): 1285 - 1293. [Abstract] [Full Text] [PDF]

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