Reversible and Irreversible Neuronal Injury Induced by Intrahippocampal Infusion of the mGluR Agonist 1S,3R-ACPD in the Rat

Abstract

Metabotropic glutamate receptor (mGluR)-induced neuronal injury in the brain was further investigated in the rat. The highly selective mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) was infused stereotaxically into the left dorsal hippocampus of adult rats. Control (2 μl saline injected) rats had minimal tissue injury that was confined to the area around the injection site. In contrast, dose of 250 nmol/2μl 1S,3R-ACPD produced a moderate number of swollen and injured cells in polymorphic, pyramidal and molecular layers of the injected hippocampus which was observed at 4 and 8 h post-injection. However, at 24 h few injured or necrotic cells were found. A dose of 1000 nmol/2μl 1S,3R-ACPD produced severe cellular injury in polymorphic, pyramidal and molecular layers of the hippocampus at 4, 8, or 24 h. At 24 h after this higher dose of 1S,3R-ACPD, a number of necrotic cells (i.e. pyramidal neurons of area CA1) were found. Both doses of 1S,3R-ACPD produced seizures in animals that were charcaterized by multiple episodes of wet dog shakes, staring, immobility, facial automatisms, rearing, bilateral forelimb clonus, and loss of postural control. These data support a possible role for excesive mGluR activation in pathological states of convulsions and neurodegeneration.