Numbers of granule cells and GABAergic boutons are correlated in shrunken sclerotic hippocampi of sea lions with temporal lobe epilepsy

A possible mechanism of temporal lobe epilepsy is insufficient inhibition of hippocampal dentate granule cells. Precipitating injuries that kill interneurons in the dentate gyrus might result in fewer inhibitory synapses with granule cells. To test this hypothesis, previous studies evaluated numbers or densities of interneurons, γ-amino butyric acid (GABA)ergic boutons, and inhibitory synapses in tissue from human patients with temporal lobe epilepsy and rodent models. However, those studies have limitations. Some of those limitations can be addressed by a large animal model. Sea lions (Zalophus californianus) can develop temporal lobe epilepsy naturally. Like humans, epileptic sea lions exhibit bilateral or unilateral hippocampal sclerosis (neuron loss) with granule cell vulnerability, but sea lions permit optimal tissue preservation and sampling, and good control subjects. To label interneuron cell bodies and GABAergic synaptic boutons, sea lion hippocampal tissue from both sexes was processed with immunohistochemistry for glutamic acid decarboxylase (GAD) and vesicular GABA transporter. Stereological techniques were used to evaluate the dentate gyrus of the entire hippocampus. Numbers of granule cells, GAD cells, and GABAergic boutons were substantially reduced in shrunken, sclerotic hippocampi. However, numbers of GABAergic boutons and granule cells were correlated. These findings indicate that, despite losses, numbers of GABAergic boutons scale with numbers of surviving granule cells.Significance Statement Temporal lobe epilepsy is a challenging clinical problem. Electrophysiological studies reveal that hippocampal dentate granule cells are insufficiently inhibited and hyperexcitable in epileptic tissue from humans and rodent models. The present stereological analysis of a large animal model (sea lions) found no evidence for disproportionate loss of dentate gyrus GABAergic boutons in temporal lobe epilepsy. These data suggest reduced inhibition of granule cells is attributable to something other than too few GABAergic boutons.