Differential vulnerability of neuronal subpopulations of the subiculum in a mouse model for mesial temporal lobe epilepsy

Abstract

Selective loss of inhibitory interneurons (INs) that promotes a shift toward an excitatory predominance may have a critical impact on the generation of epileptic activity. While research on mesial temporal lobe epilepsy (MTLE) has mostly focused on hippocampal changes, including IN loss, the subiculum as the major output region of the hippocampal formation has received comparatively little attention. Although it has been shown to occupy a key position in the epileptic network, data on cellular changes in the subiculum are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as hippocampal sclerosis and granule cell dispersion following status epilepticus (SE), we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorsoventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after SE and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), neuropeptide Y (NPY), calretinin (CR) and calbindin (CB), and in situ hybridization for glutamic acid decarboxylase (Gad) 67 mRNA at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE which was reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity could be measured in the subiculum concomitant with the hippocampus. We show a position-dependent reduction of Gad67-expressing INs by ~50% which particularly affected the PV- and to a lesser extent CR-expressing INs, whereas CB-expressing cells were unchanged. Interestingly, the density of NPY-positive neurons was increased, but double-labeling for Gad67 mRNA expression revealed that rather a de novo expression of NPY in non-GABAergic cells instead of IN changes underlay this increase. Our data reveal a position- and cell type-specific vulnerability of subicular INs in MTLE which might contribute to hyperexcitability of the subiculum, as reflected in the occurrence of epileptic activity. Keypoints (3-5)O_LIThe subiculum develops epileptic activity after intrahippocampal kainate injection in mice C_LIO_LIGad67-mRNA expressing interneurons are reduced in the subiculum in the intrahippocampal kainate model for mesial temporal lobe epilepsy C_LIO_LIParvalbumin- and calretinin-expressing interneurons are particularly vulnerable in epilepsy C_LIO_LINeuropeptide Y upregulation in non-GABAergic cells in the subiculum indicates compensatory processes C_LI