MECHANISMS OF KAINIC ACID INDUCED HIPPOCAMPAL EPILEPSY (GLUTAMIC ACID DECARBOXYLASE, EXCITOTOXIN, NEUROTOXICOLOGY)

Temporal lobe epilepsy (TLE) has a complex etiology and symptomatology not readily defined in experimental animals. The present study attempts to define the relationship(s) between limbic seizures and hippocampal pathology using the kainic acid (KA) model of epilepsy. Following an ipsilateral (KA('+)) intrahippocampal KA injection, hippocampal neuro- pathology and physiology were studied using a variety of cytological techniques and correlated physiological tests of neuronal excitability. The present KA('+) data demonstrated a selective vulnerability of CA(,3) - CA(,4) pyramidal neurons and a significant resistance of most inhibitory (GAD('+)) interneurons to the neurotoxic effects of KA, while contralateral (KA('-)) neuronal densities were equivalent to controls. Hence the present data does not support the concept of "disinhibition" in the hippocampus as a mechanism of seizure genesis. Although the exact pattern of hippocampal sclerosis differed between the intrahippocampal KA model and human TLE, the epileptogenic mechanisms may be similar, i.e., temporal lobe seizures may arise from abnormal circuitry near a focus of observable pathology. The KA-induced loss of CA(,3) and CA(,4) derived afferents to the fascia dentata inner molecular layer induced sprouting into their ipsi- and contralateral termination zones by granule cell mossy fibers and inhibitory GAD('+) interneurons, thus establishing a microanatomical basis for the presence of abnormal circuitry near a focus of observable pathology in the kainate model of epilepsy.; Electrophysiological data suggested that ipsi- and contralateral KA-induced synaptic reorganization facilitated hippocampal kindling. Similarly, the synaptic reorganization resulting from fornix and commissural transection in controls contributed to hippocampal excitability. In contrast to the controls, kainate animals with intact commissures and fornix kindled significantly faster than did the transected kainate animals. Regardless of commissural and fornix integrity, however, all KA animals kindled significantly faster than did the intact controls. Thus although both ipsilateral and contralateral hippocampi were independently epileptogenic in the kainate animals, bilateral access to KA-induced changes (e.g., bilateral synaptic reorganization) facilitates subsequent hippocampal kindling.