Synaptic and epileptiform activity of the dentate gyrus in kainate-treated rats with mossy fiber sprouting
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Description
The neurotoxin kainate produces hippocampal lesions which in turn induce the mossy fibers, the axons of the dentate granule cells, to sprout collaterals. These collaterals grow across the granule cell body layer and appear to synapse on the dendrites of the granule cells. If these synapses are functional, a recurrent excitatory circuit will have formed in the dentate. As hippocampal tissue taken from human temporal lobe epileptics show similar pyramidal cell loss and mossy fiber sprouting, the KA-treated animal has been proposed as a model for temporal lobe epilepsy (Nadler, 1981) Tauck and Nadler (1985) have presented data suggesting mossy fiber sprouting is associated with the generation of multiple population spikes in the dentate in response to hilar stimulation. Because normally only a single population spike is evoked, these data suggest the sprouted mossy fibers have formed a functional circuit. To further assess the physiology of dentate granule cells after mossy fiber sprouting, intracellular and extracellular recordings from hippocampal slices were performed As a preliminary step in examining mossy fiber sprouting in the kainate treated rat, we studied the electrically evoked responses in the dentate gyrus of normal rats under conditions of heightened excitability. After blocking GABA$\sb{\rm A}$ receptors with bicuculline (30 $\mu$M), a second population spike was evoked to hilar stimulation. In higher concentrations of GABA$\sb{\rm A}$ blockers (100 $\mu$M bicuculline or picrotoxin), three to four population spikes were evoked to hilar stimulation. After raising (K$\sp+$) from 3 to 10 mM in 30 $\mu$M bicuculline, four to five population spikes were evoked. These data indicate multiple population spikes to hilar stimulation do not require mossy fiber sprouting Experiments conducted on kainate-treated rats revealed that in normal medium hippocampal slices from both animals with and without mossy fiber sprouting had normal responses. When GABA$\sb{\rm A}$ responses were blocked with 30 $\mu$M bicuculline, rats with mossy fiber sprouting showed bursts of population spikes after long and variable delays to low-intensity hilar stimulation. Some slices from hippocampi with mossy fiber sprouting also showed spontaneous population bursts in bicuculline. These responses were not seen in treated animals which did not sprout mossy fiber collaterals. Based on computer simulations and experiments on other brain areas, these responses suggest local recurrent excitatory circuits have formed. These data also argue that the responses of the dentate gyrus with mossy fiber sprouting are normal, and show abnormality only when inhibition is depressed Mossy fiber sprouting has been documented in human tissue taken from temporal lobe epileptics (Houser et al., 1990). We have developed methods for assessing mossy fiber sprouting in tissue taken from humans during surgery for intractable epilepsy