Hippocampal injury, atrophy, synaptic reorganization, and epileptogenesis after perforant pathway stimulation-induced status epilepticus in the mouse.

Prolonged dentate granule cell discharges produce hippocampal injury and chronic epilepsy in rats. In preparing to study this epileptogenic process in genetically altered mice, we determined whether the background strain used to generate most genetically altered mice, the C57BL/6 mouse, is vulnerable to stimulation-induced seizure-induced injury. This was necessary because C57BL/6 mice are reportedly resistant to the neurotoxic effects of kainate-induced seizures, which we hypothesized to be related to strain differences in kainate's effects, rather than genetic differences in intrinsic neuronal vulnerability. Bilateral perforant pathway stimulation-induced granule cell discharge for 4 hours under urethane anesthesia produced degeneration of glutamate receptor subunit 2 (GluR2)-positive hilar mossy cells and peptide-containing interneurons in both FVB/N (kainate-vulnerable) and C57BL/6 (kainate-resistant) mice, indicating no strain differences in neuronal vulnerability to seizure activity. Granule cell discharge for 2 hours in C57BL/6 mice destroyed most GluR2-positive dentate hilar mossy cells, but not peptide-containing hilar interneurons, indicating that mossy cells are the neurons most vulnerable to this insult. Stimulation for 24 hours caused extensive hippocampal neuron loss and injury to the septum and entorhinal cortex, but no other detectable damage. Mice stimulated for 24 hours developed hippocampal sclerosis, granule cell mossy fiber sprouting, and chronic epilepsy, but not the granule cell layer hypertrophy (granule cell dispersion) produced by intrahippocampal kainate. These results demonstrate that perforant pathway stimulation in mice reliably reproduces the defining features of human mesial temporal lobe epilepsy with hippocampal sclerosis. Experimental studies in transgenic or knockout mice are feasible if electrical stimulation is used to produce controlled epileptogenic insults.

Impairment of in vivo theta-burst long-term potentiation and network excitability in the dentate gyrus of synaptopodin-deficient mice lacking the spine apparatus and the cisternal organelle.

The function of the spine apparatus in dendritic spines and the cisternal organelles in axon initial segments is little understood. The actin-associated protein, synaptopodin, is essential for the formation of these organelles which are absent in synaptopodin -/- mice. Here, we used synaptopodin -/- mice to explore the role of the spine apparatus and the cisternal organelle in synaptic plasticity and local circuit excitability in response to activation of the perforant path input to the dentate gyrus in vivo. We found impaired long-term potentiation following theta-burst stimulation, whereas tetanus-evoked LTP was unaffected. Furthermore, paired-pulse inhibition of the population spike was reduced and granule cell excitability was enhanced in mutants, hence revealing an impairment of local network inhibition. In summary, our data represent the first electrophysiological evidence that the lack of the spine apparatus and the cisternal organelle leads to a defect in long-term synaptic plasticity and alterations in local circuit control of granule cell excitability under adult in vivo conditions.

Excitotoxic hippocampal neuron loss following sustained electrical stimulation of the perforant pathway in the mouse.

Prolonged electrical stimulation of the perforant pathway in the rat evokes epileptiform discharges in dentate granule cells and irreversibly damages hilar neurons. In this in vivo study, we demonstrate that similar perforant path stimulation in C57Bl/6 mice causes the same pattern of hippocampal neuron loss. Therefore, this mouse model of seizure-induced hippocampal injury can be used for a wide variety of studies in genetically altered conditions not available in rats.