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

• Published in: Frontiers in cellular neuroscience Vol. 17; p. 1142507
• Main Authors: Franz, Julia, Barheier, Nicole, Wilms, Henrike, Tulke, Susanne, Haas, Carola A, Häussler, Ute
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 29.03.2023; Frontiers Media S.A
• Subjects: Brain; Calretinin; Convulsions & seizures; dorso-ventral axis; Epilepsy; Fluorescence in situ hybridization; FluoroJade C; Gene expression; Glutamate decarboxylase; Glutamic acid; Hippocampus; Immunohistochemistry; Interneurons; intrahippocampal kainate; Neuropeptide Y; Neuroscience; Parvalbumin; Patients; Sclerosis; Subiculum; Surgery; Temporal lobe; γ-Aminobutyric acid; United Kingdom > UK; United States > US; Germany; parvalbumin; neuropeptide Y; FluoroJade C; calretinin; dorso-ventral axis; intrahippocampal kainate; epileptic activity
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2023.1142507

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 less attention. The subiculum has been shown to occupy a key position in the epileptic network, but data on cellular alterations are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as unilateral hippocampal sclerosis and granule cell dispersion, we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorso-ventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after (SE), fluorescence hybridization for glutamic acid decarboxylase ( mRNA and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY) at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE, reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity occurred in the subiculum concomitantly with the hippocampus. In addition, we show a position-dependent reduction of -expressing INs by ∼50% (along the dorso-ventral as well as transverse axis of the subiculum). This particularly affected the PV- and to a lesser extent CR-expressing INs. The density of NPY-positive neurons was increased, but the double-labeling for mRNA expression revealed that an upregulation or expression of NPY in non-GABAergic cells with a concomitant reduction of NPY-positive INs underlies this observation. Our data suggest a position- and cell type-specific vulnerability of subicular INs in MTLE, which might contribute to hyperexcitability of the subiculum, reflected in epileptic activity.