Abstracts

Mechanisms of hyperexcitability in hilar ectopic granule cells

Abstract number : IW.26;
Submission category : 1. Translational Research
Year : 2007
Submission ID : 8160
Source : www.aesnet.org
Presentation date : 11/30/2007 12:00:00 AM
Published date : Nov 29, 2007, 06:00 AM

Authors :
J. Nadler1, R. Z. Zhan1, Y. Jiao1

Rationale: Many of the new granule cells produced as a result of seizures migrate aberrantly into the dentate hilus. These neurons (HEGCs) integrate into the novel granule cell network of epileptic brain and were reported to burst spontaneously. Because HEGCs may be important for seizure propagation through the dentate gyrus, this study investigated mechanisms that regulate their excitability.Methods: Pilocarpine-treated rats were studied 10-40 weeks after prolonged (6-8 h) status epilepticus. Whole cell and perforated patch recordings were made from HEGCs and normally-located dentate granule cells in hippocampal slices. The number of putative HEGCs was determined with use of GluR2 immunocytochemistry and quantitative stereology.Results: HEGCs accounted for ~62% of all hilar neurons in these animals. Most of them fired in two modes: action potentials having a large afterdepolarization usually intermixed with bursts and repetitive action potentials without a large afterdepolarization. There was a voltage-dependent transition between these firing modes. Bursting depended on the activation of a large T-type Ca2+ current. Spike frequency adaptation was not evident in spontaneously firing/bursting HEGCs. HEGCs received little inhibitory innervation, as evidenced by small mossy fiber-evoked IPSCs and a very low frequency of mIPSCs. Nevertheless, the charge transferred per second by sIPSCs was only 36% less than in control granule cells and tonic inhibitory current density was ~9 times control. The large tonic inhibitory current could be explained by enhanced GABA release, possibly related to increased spontaneous firing of the remaining interneurons, and involvement of multiple GABAA receptor subtypes, but not by impaired GABA transport.Conclusions: Most HEGCs possess intrinsic burst capability dependent on retention of the large T-type Ca2+ current characteristic of immature granule cells. They have a relatively normal baseline level of GABA inhibitory current, despite their sparse inhibitory innervation, but evoked feedback inhibition is subnormal. The overall effect may be to reduce spontaneous firing/bursting, but to enhance the probability of activation by excitatory synaptic activity. These properties support a role for HEGCs in facilitating seizure propagation. (Source of funding: NIH grant NS038108)
Translational Research