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The Journal of Neuroscience, October 18, 2006, 26(42):10756-10767; doi:10.1523/JNEUROSCI.2323-06.2006

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Neurobiology of Disease
GABAergic Synaptic Inhibition Is Reduced before Seizure Onset in a Genetic Model of Cortical Malformation

Stacey A. Trotter,¹ Jaideep Kapur,² Matthew J. Anzivino,¹ and Kevin S. Lee¹

Departments of ¹Neuroscience and ²Neurology, Health Sciences Center, Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia 22908

Correspondence should be addressed to Dr. Kevin S. Lee, Department of Neuroscience, University of Virginia, P.O. Box 800394, Charlottesville, VA 22908. Email: ksl3h{at}virginia.edu

Malformations of the neocortex are a common cause of human epilepsy; however, the critical issue of how disturbances in cortical organization render neurons epileptogenic remains controversial. The present study addressed this issue by studying inhibitory structure and function before seizure onset in the telencephalic internal structural heterotopia (tish) rat, which is a genetic model of heightened seizure susceptibility associated with a prominent neocortical malformation. Both normally positioned (normotopic) and misplaced (heterotopic) pyramidal neurons in the tish neocortex exhibited lower resting membrane potentials and a tendency toward higher input resistance compared with pyramidal neurons from control brains. GABAergic synaptic transmission was attenuated in the tish cortex, characterized by significant reductions in the frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs recorded from pyramidal neurons. In addition, the amplitudes of sIPSCs were reduced in the tish neocortex, an effect that was more profound in the normotopic cells. Immunohistochemical assessment of presynaptic GABAergic terminals showed a reduction in terminals surrounding pyramidal cell somata in normotopic and heterotopic tish neocortex. The attenuation of inhibitory innervation was more prominent for normotopic neurons and was associated with a reduction in a subset of GABAergic interneurons expressing the calcium-binding protein parvalbumin. Together, these findings indicate that key facets of inhibitory GABAergic neurotransmission are disturbed before seizure onset in a brain predisposed to developing seizures. Such alterations represent a rational substrate for reduced seizure thresholds associated with certain cortical malformations.

Key words: GABA_A receptor; cerebral cortex; interneuron; inhibition; pyramidal cell; epilepsy

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Received June 1, 2006; revised Aug. 30, 2006; accepted Sept. 4, 2006.

Correspondence should be addressed to Dr. Kevin S. Lee, Department of Neuroscience, University of Virginia, P.O. Box 800394, Charlottesville, VA 22908. Email: ksl3h{at}virginia.edu

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