Electroencephalographic, behavioral, and neuropathologic changes were monitored after infusions of the endogenous excitatory amino acid, quinolinic acid (QUIN), into the dorsal hippocampus of unanesthetized, freely moving rats. A dose of 120 nmol QUIN was required to reliably precipitate seizures although EEG changes were observed with doses as small as 3 nmol. Seizure episodes were characterized by repetitive periods of high-voltage spiking typically lasting 20 s but occasional longer multicomponent episodes (60 s) were also observed. The latency of specific QUIN-induced seizures was similar for all doses tested (19 to 32 min); however, the total number of seizures and total time in seizures increased in a dose-dependent fashion from 30 to 300 nmol QUIN. Seizure episodes were often associated with a frozen appearance of the animal and intermittent "wet dog shakes". Ataxia was apparent in animals receiving 120 and 300 nmol QUIN. Using light microscopic analyses, pyramidal cell degeneration was observed in the QUIN-injected hippocampus (CA3 and CA1 cells more susceptible than CA2 cells); dentate granule cells showed signs of degeneration only at the largest QUIN dose. No neuropathologic changes were found outside the injected hippocampus. Seizures and neuropathologic changes induced by 120 nmol QUIN were completely blocked by pre- or cotreatment with 12 nmol (-)2-amino-7-phosphonoheptanoic acid. Experiments with [3H]QUIN indicated that only 3% of the injected radioactivity was present in the dorsal hippocampus at the average time of seizure onset (25 min), and consisted entirely of unmetabolized QUIN. The potent convulsant properties of QUIN, an endogenous metabolite, may prove to be of relevance for the etiology of human temporal lobe epilepsy.
ASJC Scopus subject areas
- Developmental Neuroscience