Kainic acid neurotoxicity toward hippocampal formation: Dependence on specific excitatory pathways

Abstract

Rat hippocampal neurons are extremely sensitive to the neurotoxic action of the potent convulsant, kainic acid. It has been suggested that kainic acid destroys neurons through a specific interaction with excitatory glutamatergic afferent fibers. We have tested this hypothesis by making selective lesions of putatively glutamatergic or non-glutamatergic hippocampal afferent fibers three days prior to injecting kainic acid either intraventricularly or directly into the hippocampal formation. Both destruction of hippocampal mossy fibers with colchicine and transection of these fibers markedly reduced the subsequent toxicity of intraventricular kainic acid toward CA3 neurons, but degeneration of the mossy fibers conferred no protection against kainic acid injected locally. Conversely, removal of projections from the entorhinal cortex or medial septum protected dentate granule cells and all but the most medial CA1 pyramidal cells from destruction by locally injected kainic acid, but did not alter the hippocampal toxicity of intraventricular kainic acid. A commissurotomy little affected the hippocampal lesion made by either route of administration. Both intraventricularly and locally injected kainic acid destroyed neurons in extrahippocampal limbic regions. The pattern of damage could not be accounted for merely by diffusion of the toxin from the site of injection. All four types of hippocampal deafferentation markedly attenuated this extrahippocampal toxicity. These results emphasize the dependence of kainic acid neurotoxicity on specific excitatory circuitry. The identity of the critical circuit depends on the route by which kainic acid is administered, but not on the use of glutamate as a transmitter. We suggest that kainic acid destroys neurons indirectly, by initiating a prolonged status epilepticus that is lethal to seizure-sensitive neurons, such as the hippocampal pyramidal cells.