Abstracts

RATIONALE: In previous studies, we have shown that in immature rats kainic acid (KA)-induced seizures lead to a selective loss of CA1 interneurons in the oriens/alveus layer. This was associated with a loss of hippocampal function as shown with the Morris Water Maze test. The selective mGluR1 antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA) was able to reverse the effects of KA on hippocampal functions and limit the loss of interneurons. In mature rats, KA-induced seizures lead to a similar loss of hippocampal functions but with extensive loss of both interneurons and principal cells. The present study was undertaken to evaluate the neuroprotective effects of AIDA on the anatomical and cognitive consequences of the KA-induced seizures in mature rats.
METHODS: Sprague-Dawley rats aged postnatal day 60 (P60) were given two sub-convulsive doses of KA (8.0 mg/kg) intraperiteonally (i.p.) at one-hour intervals. Another group received two doses of KA plus simultaneously AIDA (1.8 mg/kg) i.p. Control rats received an equivalent volume of either AIDA (1.8 mg/kg) alone or a saline solution. Initial and recurrent seizures were monitored using daily video-recordings. Hippocampal function was tested 45 days after the KA-induced prolonged seizures with the Morris Water Maze test. In this procedure, we measured the latency for the rats to escape from the water onto a hidden platform. Morphological changes were assessed 60 days post-injection. In one hemisphere, Cresyl violet staining was performed. The other hemisphere was stained for immunofluorescence with anti-parvalbumin (PV) polyclonal and anti- somatostatin (SS) monoclonal antibodies to label inhibitory interneurons.
RESULTS: In the Morris Water Maze test, the KA rats took more time to reach the platform than the KA+A group. But KA+A rats still performed worst than controls. Cresyl violet staining revealed a complete loss of CA1 and CA3 pyramidal cells in the KA rats and a marked thickening of the granule cell layer. This was associated with a marked sclerosis of all the hippocampal structures. In KA+A rats, most of the CA3 pyramidal and hilar cells were lost but the anatomical landmarks were still recognisable. In CA1 pyramidal cells, neuronal loss was partially blocked by AIDA. Immunofluorescence staining also showed a marked reduction in the number of PV- and SS-containing cells in both the CA3 pyramidal cell layer and in the CA1 oriens/alveus strata in the KA rats.
CONCLUSIONS: The metabotropic glutamate receptor antagonist AIDA limits some of the cognitive and morphological impairments of the kainate-induced seizures in mature rats. This neuroprotective effect appears however to be less robust than in the immature rat. This would be consistent with the developmental profile of class I metabotropic glutamate receptors.
[Supported by: Savoy Foundation for Epilepsy.]