Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine.

Despite numerous neuroendocrinological studies of seizures, the influence of estrogen and progesterone on seizures and epilepsy remains unclear. This may be due to the fact that previous studies have not systematically compared distinct endocrine conditions and included all relevant controls. The goal of the present study was to conduct such a study using pilocarpine as chemoconvulsant. Thus, age and weight-matched, intact or ovariectomized rats were tested to determine incidence of status epilepticus and to study events leading to status. Intact female rats were sampled at each cycle stage (proestrus, estrus, metestrus, or diestrus 2). Convulsant was administered at the same time of day, 10:00-10:30 a.m. Statistical analysis showed that there was a significantly lower incidence of status on the morning of estrus, but differences were attenuated in older animals. Ovariectomized rats were distinct in their rapid progression to status. These results show that the incidence of status in female rats following pilocarpine injection, and the progression to pilocarpine-induced status, are influenced by reproductive state as well as age. The hormonal milieu present specifically on the morning of estrus appears to decrease susceptibility to pilocarpine-induced status, particularly at young ages. In contrast, the chronic absence of reproductive steroids that characterizes the ovariectomized rat leads to a more rapid progression to status. This dissociation between incidence vs. progression provides new insight into the influence of estrogen and progesterone on seizures.

Preemptive low-frequency stimulation decreases the incidence of amygdala-kindled seizures.

PURPOSE: The use of electrical stimulation as a therapy for epilepsy is currently being studied in experimental animals and in patients with epilepsy. This study examined the effect of preemptive, low-frequency, 1-Hz sine wave stimulation (LFS) on the incidence of amygdala-kindled seizures in the rat. METHODS: Electrodes were implanted into the basolateral amygdalae of adult male rats. All animals received a kindling stimulus of 60-Hz, 400-microA, sine wave for 1 s twice a day. Experimental animals received an additional LFS consisting of 1 Hz, 50 microA for 30 s immediately before the kindling stimulus. Afterdischarge (AD) duration, behavioral seizure score, the number of stimulations required to elicit the first stage five seizure and to become fully kindled were measured. After 20 stimulations, a crossover procedure was performed. Fully kindled rats from each group were switched, so that the original controls received LFS plus the kindling stimulus, and the original experimental rats received only the kindling stimulus. RESULTS: During kindling acquisition, LFS induced a significant decrease in AD duration. A significant increase in the number of times the kindling stimulus failed to elicit an AD was noted. Control rats exhibited an AD 99% of the time compared with 70% in experimental rats (p < 0.0001; Fisher's Exact test). In fully kindled animals, the incidence of stage five seizures in the original controls significantly decreased from 98% to 42% (p < 0.0001) when the LFS was added to the kindling paradigm. CONCLUSIONS: The dramatic decrease in the incidence of stage 5 seizures in fully kindled animals after preemptive LFS strongly suggests that LFS may be an effective therapy for the prevention of seizures in patients with epilepsy.

Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting.

Mossy fiber sprouting is a form of synaptic reorganization in the dentate gyrus that occurs in human temporal lobe epilepsy and animal models of epilepsy. The axons of dentate gyrus granule cells, called mossy fibers, develop collaterals that grow into an abnormal location, the inner third of the dentate gyrus molecular layer. Electron microscopy has shown that sprouted fibers from synapses on both spines and dendritic shafts in the inner molecular layer, which are likely to represent the dendrites of granule cells and inhibitory neurons. One of the controversies about this phenomenon is whether mossy fiber sprouting contributes to seizures by forming novel recurrent excitatory circuits among granule cells. To date, there is a great deal of indirect evidence that suggests this is the case, but there are also counterarguments. The purpose of this study was to determine whether functional monosynaptic connections exist between granule cells after mossy fiber sprouting. Using simultaneous recordings from granule cells, we obtained direct evidence that granule cells in epileptic rats have monosynaptic excitatory connections with other granule cells. Such connections were not obtained when age-matched, saline control rats were examined. The results suggest that indeed mossy fiber sprouting provides a substrate for monosynaptic recurrent excitation among granule cells in the dentate gyrus. Interestingly, the characteristics of the excitatory connections that were found indicate that the pathway is only weakly excitatory. These characteristics may contribute to the empirical observation that the sprouted dentate gyrus does not normally generate epileptiform discharges.