Local and distant neuronal degeneration following intrastriatal injection of kainic acid.

Abstract

After intrastriatal injection, the neurotoxin, kainic acid, was cleared from the rat forebrain in a biphasic manner with 70% eliminated within 2 hours; by 24 hours after infusion, less than 1% of the kainic acid remained in the forebrain. The kainic acid diffused into adjacent brain structures, achieving mu molar concentrations in several regions ipsilateral to the injected striatum. At various times after intrastriatal injection of 9.3 nmoles of kainic acid, the brain was serially sectioned; the sections were stained for Nissl substance with cresyl violet or for degenerating neurons with the ammoniacal silver method. Neuronal degeneration spread unevenly into contiguous structures from the central sphere in the injected striatum and affected the ipsilateral pyriform cortex and amygdala, the deep layers of the overlying cerebral cortex, and the medial aspects of the bed nucleus of the stria terminalis and of the nucleus accumbens. In half of the rats, the pyriform cortex contralateral to the side of injection also underwent degeneration. A subpopulation of pyramidal cells in layer IV of the lateral neocortex and the CA3-CA4 pyramidal cells in the ipsilateral hippocampus were selectively affected, whereas adjacent neurons remained intact. The distribution of agyrophilic fibers and terminals in subcortical structures was consistent with the degeneration of neurons of origin in the affected striatal and extrastriatal regions. Brain sections stained by the gold sublimate technique from rats perfused 20 days after injection revealed an intense astrocytic response in all areas affected by acute neuronal degeneration. Extrastriatal damage could be markedly reduced by injection of lower doses of kainic acid (2.3 nmoles) with brief anesthesia; under these conditions, however, the subpopulation of large striatal neurons were relatively resistant, as compared to the Golgi II neurons. These studies demonstrate significant and variable neuronal degeneration beyond the primary site of the lesion after intracerebral injection of kainic acid; several factors affect the pattern of degeneration, including the amount of kainic acid injected, its biological activity, its diffusion, duration of anesthesia, and variable sensitivity of neurons. Consequently, care must be exercised in the use of this neurotoxin to determine the extent and selectivity of neuronal damage, particularly with reference to neuronal vulnerability beyond the central sphere of intrinsic neuronal degeneration.