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The Journal of Neuroscience, April 1, 2003, 23(7):2759

Spontaneous Seizures and Loss of Axo-Axonic and Axo-Somatic Inhibition Induced by Repeated Brief Seizures in Kindled Rats

Umit Sayin^{1, *}, Susan Osting^{2, *}, Joshua Hagen^{1, *}, Paul Rutecki^{1, 3, 4}, and Thomas Sutula^{1, 2}

Departments of ¹ Neurology, ² Anatomy, and ³ Neurological Surgery, University of Wisconsin, and ⁴ The William S. Middleton Veterans Administration Hospital, Madison, Wisconsin 53792

Repeated brief seizures evoked by kindling progressively increase seizure susceptibility and eventually induce spontaneous seizures. Previous studies have demonstrated that the initial seizures evoked by kindling increase paired-pulse inhibition at 15-25 msec interpulse intervals in the dentate gyrus and also induce apoptosis, progressive neuronal loss, mossy fiber sprouting, and neurogenesis, which could potentially alter the balance of excitation and/or inhibition and modify functional properties of hippocampal circuits. In these experiments, paired-pulse inhibition in the dentate gyrus was reduced or lost after ~90-100 evoked seizures in association with emergence of spontaneous seizures. Evoked IPSCs examined by single electrode voltage-clamp methods in granule cells from kindled rats experiencing spontaneous seizures demonstrated altered kinetics (reductions of ~48% in 10-90% decay time, ~40% in , and ~65% in charge transfer) and confirmed that decreased inhibition contributed to the reduced paired-pulse inhibition. The loss of inhibition was accompanied by loss of subclasses of inhibitory interneurons labeled by cholecystokinin and the neuronal GABA transporter GAT-1, which project axo-somatic and axo-axonic GABAergic inhibitory terminals to granule cells and axon initial segments. Seizure-induced loss of interneurons providing axo-somatic and axo-axonic inhibition may regulate spike output to pyramidal neurons in CA3 and could play an important role in generation of spontaneous seizures. The sequence of progressive cellular alterations induced by repeated seizures, particularly loss of GABAergic interneurons providing axo-somatic and axo-axonic inhibition, may be important in the development of intractable epilepsy.

Key words: hippocampus; dentate gyrus; GABA; CCK; GAT-1; damage; epilepsy

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^* U.S., S.O., and J.H. contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372759-10$05.00/0

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