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Genetic influences contribute to susceptibility to seizures and to excitotoxic injury, but it is unclear if/how these susceptibilities are linked. This study assessed the impact of genetic background on mouse strain seizure susceptibility, seizure phenotype, mortality, and hippocampal histopathology. A subcutaneous (s.c.) kainic acid multiple injection protocol was developed. Five mouse strains were tested: a and b) C57BL/6J and 129/SvJ, strains commonly used in gene targeting experiments; c) C3HeB/FeJ, a strain with reported sensitivity to the convulsant effects of kainic acid (KA); d) 129/SvEms, a strain reportedly susceptible to hippocampal excitotoxic cell death; and e) a mixed genetic background strain (129/SvJXC57BL/6J) from which targeted gene deletion experiments have been carried out. Histopathological features were examined at early (7-10 day), delayed (2-4 month), and late (6-13 month) time points.Mouse background strains can be genetically segregated based on excitotoxin sensitivity, seizure phenotype, mortality, and hippocampal histopathology. When injected with KA, C3HeB/FeJ and C57BL/6J strains were resistant to cell death and synaptic reorganization despite severe behavioral seizures, while 129/SvEms mice developed marked pyramidal cell loss and mossy fiber sprouting despite limited seizure activity. The mixed background 129/SvJXC57BL/6J group exhibited features of both parental strains. In the mouse strains tested, the duration or severity of seizure activity was not predictive of subsequent hippocampal pyramidal cell death and/or synaptic reorganization. Unlike rats, mice exhibiting prolonged high-grade KA-induced seizure activity did not develop subsequent spontaneous behavioral seizures.

The GABAA antagonist bicuculline methiodide and the GABAB antagonist phaclofen were used to examine the function of the fast inhibitory postsynaptic potential and slow inhibitory postsynaptic potential, in hippocampal slice cultures in the rat. These cultures form easily-visualized monolayers of nerve cells which maintain the structure and synaptic organization of transverse hippocampal slices. The present study shows that the cellular and synaptic physiological properties of slice cultures are very similar, but not identical, to those observed in acutely-prepared hippocampal slices. The major difference is a higher incidence of fast excitatory postsynaptic potentials and inhibitory postsynaptic potentials compared to slices, and the appearance of spontaneous slow inhibitory postsynaptic potentials. This increase in synaptic drive has been useful for our investigation of the role of GABA-mediated inhibitory postsynaptic potentials. Bath application of 10 microM bicuculline blocked the fast inhibitory postsynaptic potentials and gave rise to bursts 1-11 s in duration. The presence of the slow inhibitory postsynaptic potentials did not prevent bicuculline-induced burst activity. Phaclofen (1 mM) perfused in the bath reversibly blocked the slow inhibitory postsynaptic potential, but did not result in the formation of large paroxysmal depolarizing shift-like bursts as seen with bicuculline. Rather, block of the slow inhibitory postsynaptic potential resulted in the formation of repetitive "afterdischarge bursts". These afterdischarge potentials typically appeared with a delay of 2-15 min following block of the slow inhibitory postsynaptic potential, during which time there was a gradual increase in non-synchronized excitatory activity. Once established, this cycle of increasing excitatory activity culminating in afterdischarge potentials recurred at 2-4 min intervals while phaclofen was present.(ABSTRACT TRUNCATED AT 250 WORDS)