Abstract
The loss of hippocampal interneurons has been considered as one reason for the onset of temporal lobe epilepsy (TLE) by shifting the excitation-inhibition balance. Yet, there are many different interneuron types which show differential vulnerability in the context of an epileptogenic insult. We used the intrahippocampal kainate (KA) mouse model for TLE in which a focal, unilateral KA injection induces status epilepticus (SE) followed by development of granule cell dispersion (GCD) and hippocampal sclerosis surrounding the injection site but not in the intermediate and temporal hippocampus. In this study, we characterized the loss of interneurons with respect to septotemporal position and to differential vulnerability of interneuron populations. To this end, we performed intrahippocampal recordings of the initial SE, in situ hybridization for glutamic acid decarboxylase 67 (GAD67) mRNA and immunohistochemistry for parvalbumin (PV) and neuropeptide Y (NPY) in the early phase of epileptogenesis at 2 days and at 21 days after KA injection, when recurrent epileptic activity and GCD have fully developed. We show that SE extended along the entire septotemporal axis of both hippocampi, but was stronger at distant sites than at the injection site. There was an almost complete loss of interneurons surrounding the injection site and expanding to the intermediate hippocampus already at 2 days but increasing until 21 days after KA. Furthermore, we observed differential vulnerability of PV- and NPY-expressing cells: while the latter were lost at the injection site but preserved at intermediate sites, PV-expressing cells were gone even at sites more temporal than GCD. In addition, we found upregulation of GAD67 mRNA expression in dispersed granule cells and of NPY staining in ipsilateral granule cells and ipsi- and contralateral mossy fibers. Our data thus indicate differential survival capacity of interneurons in the epileptic hippocampus and compensatory plasticity mechanisms depending on the hippocampal position.
Highlights
Interneurons play a crucial role in balancing neuronal activity in the brain
We show that in the ipsilateral septal hippocampus most glutamic acid decarboxylase 67 (GAD67) mRNA-expressing interneurons were lost already at 2 days after KA injection except for a small population of interneurons in CA3 including PV- and neuropeptide Y (NPY)-positive cells
In the intermediate hippocampus we observed a differential vulnerability of the different interneuron populations: PV-expressing cells were lost at much more temporally located areas than NPY-expressing cells
Summary
Interneurons play a crucial role in balancing neuronal activity in the brain. In epilepsy the loss of inhibitory interneurons has been associated with the emergence of epileptic seizures (for review, see Lopes da Silva et al, 1994; Olsen and Avoli, 1997; Fritschy, 2008). There are controversial reports in the literature ranging from substantial loss of PV-expressing cells (Bouilleret et al, 2000a), to a transient loss of PV expression (Sloviter et al, 1991; Wittner et al, 2001) or only marginal reduction of PV-expressing cells (Wyeth et al, 2010), depending on the hippocampal region, the degree of hippocampal sclerosis and the particular patient or animal model Another interneuron population which is partially lost in TLE expresses the co-transmitter NPY (Sloviter and Lowenstein, 1992; Sperk et al, 1992; Kuruba et al, 2011). In addition to the loss of NPY-expressing cells in TLE, the upregulation of NPY in granule cells and mossy fibers has been described in several animal models (Sperk et al, 1992; Makiura et al, 1999; Vezzani et al, 1999; Arabadzisz et al, 2005), most likely reflecting a compensatory mechanism
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