Host: The Japanese Society of Toxicology
Central nervous system (CNS) toxicity is a critical factor in the possible adverse effects in drug development. Seizures and convulsions are frequent manifestations of CNS toxicity and are the leading cause of drug development attrition. Conventional behavioral batteries such as the Irwin test and the functional observational battery (FOB) are used to examine toxicity. While they are useful to evaluate animals' locomotor and overall health conditions, they overlook specific CNS toxicity. Thus, assay systems that can assess neural mechanisms' underlying CNS toxicity are critical. Recently, several laboratories have developed in vitro electrophysiological assay systems using hippocampal brain slices from various animal species (rats, dogs, monkeys, and mini pigs) for seizure liability assessment. Here, we report a novel assay system using VSD imaging in the mouse hippocampus. We applied electrical stimulation to the Schaffer collateral pathway from a stimulation electrode placed near the CA1/CA3 border. CA1 responses were recorded every thirty seconds with an imaging system (MiCAM02, Brainvision Ltd.) and field potential recordings from the stratum radiatum. Four positive control substances of picrotoxin, SR95331 (Gabazine), 4-aminopyridine, and pilocarpine were tested. All of them induce seizures or convulsions in animals. The VSD responses were significantly different in these substances. The various effects on CA1 activity indicate that the system can evaluate neural mechanisms, thus examining CNS toxicity.
