Selective loss of GABA neurons in area CA1 of the rat hippocampus after intraventricular kainate

Abstract

The intraventricular injection of kainic acid (KA) in rats produces a loss of dentate hilar neurons and hippocampal CA3 pyramidal cells, and renders the dentate granule cells and the CA1 pyramidal cells hyperexcitable. We have used immunocytochemical detection of glutamic acid decarboxylase (GAD), a marker of γ-aminobutyric acid (GABA) cells, as well as stereological cell counting techniques, to determine whether inhibitory cell loss was present 2 weeks after KA treatment. In area CA1, we found that the density of GAD-positive cells was reduced by KA, but only in stratum oriens and the alveus. Counts of Nissl-stained neurons were also significantly reduced in this layer. These results demonstrate a loss of GABA cells in the basal dendritic layer of the CA1 region, which may underlie the hyperexcitability of CA1 pyramidal cells following KA treatment.

Introduction

The kainic acid (KA) model is widely used as an experimental model of human temporal lobe epilepsy because intracerebroventricular injection of KA produces a loss of dentate hilar cells and hippocampal CA3 pyramidal cells similar to that observed in the human epileptic hippocampus (Ben-Ari, 1985).

In rats, surviving CA1 pyramidal cells become hyperexcitable (Nadler, 1981, Ben-Ari, 1985, Williams et al., 1993, Perez et al., 1996). This pyramidal cell hyperexcitability may be due to increased N-methyl-D-aspartate (NMDA) excitatory synaptic transmission (Turner and Wheal, 1991), and to diminished polysynaptic γ-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission (Franck et al., 1988, Williams et al., 1993, Perez et al., 1996). A selective loss of somatostatin- and parvalbumin-like immunoreactivity has also been seen after KA (Best et al., 1993, Best et al., 1994) and in other models of epilepsy (Sloviter, 1987, Robbins et al., 1991, Houser and Esclapez, 1996). However, immunohistochemical studies have reported that GABAergic inhibitory cells are not lost after KA treatment (Franck et al., 1988, Davenport et al., 1990), as well as in human temporal lobe epilepsy (Babb et al., 1989).

To determine whether GABAergic cells were lost in area CA1 after KA treatment, we counted the number of interneurons immunostained for the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), in different layers of the CA1 area: (1) in stratum oriens and the alveus (O/A); (2) in stratum pyramidale (PYR); and (3) in strata radiatum and lacunosum-moleculare (R/LM), in control and KA-treated rats. Our results indicate that some GABAergic interneurons located in O/A are vulnerable to KA.