AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced hippocampal dysfunction

Purpose: In the developing animal, intraperitoneal injections of kainic acid (KA) lead to a prolonged initial seizure followed by chronic recurrent seizures and long-term hippocampal dysfunction. We investigated whether the class I metabotropic glutamate receptor (mGluR) antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA) is neuroprotective in the KA model of epilepsy. Methods: Immature rats aged postnatal day 20 (P20) and P30 were injected with fixed volumes of KA, KA + AIDA, AIDA, or saline. We monitored recurrent seizures. Thirty days later, we tested hippocampal function with the Morris water-maze test or prepared hippocampal slices to record extracellularly evoked and spontaneous potentials from the CA1 area. In a third group, we performed neuronal counts. Results: In both age groups, acute seizures were similar in KA and KA + AIDA groups. Rare spontaneous recurrent seizures occurred only in KA-injected rats. The KA P20 group performed significantly worse than controls in the water-maze test. The KA + AIDA group showed impaired performance on day 1, but learning improved substantially, reaching control values in the remaining 3 days. The P30 KA rats performed worse than controls on all trial days, whereas the KA + AIDA rats improved by day 3, but did not reach control values. Electrophysiologic recordings showed small but consistent differences between KA and control animals, suggestive of an adaptive modification in the gamma-aminobutyric acid (GABA)ergic system, reversed by AIDA. On histology, we observed a loss of CA1 interneurons in both ages. Cell loss was reversed by the use of AIDA. Conclusions: Blockade of the class I mGIuR during KA-induced seizures in the developing brain limits seizure-induced hippocampal dysfunction.