Early loss of interneurons and delayed subunit‐specific changes in GABAA‐receptor expression in a mouse model of mesial temporal lobe epilepsy

Abstract

Unilateral injection of kainic acid (KA) into the dorsal hippocampus of adult mice induces spontaneous recurrent partial seizures and replicates histopathological changes observed in human mesial temporal lobe epilepsy (MTLE) (Bouilleret V et al., Neuroscience 1999; 89:717-729). Alterations in pre- and postsynaptic components of GABAergic neurotransmission were investigated immunohistochemically at different time points (1-120 days) in this mouse model of MTLE. Markers of GABAergic interneurons (parvalbumin, calbindin-D28k, and calretinin), the type-1 GABA transporter (GAT1), and major GABA(A)-receptor subunits expressed in the hippocampal formation were analyzed. Acutely, KA injection produced a profound loss of hilar cells but only limited damage to CA1 and CA3 pyramidal cells. In addition, parvalbumin and calbindin-D28k staining of interneurons disappeared irreversibly in CA1 and dentate gyrus (DG), whereas calretinin staining was spared. The prominent GABA(A)-receptor alpha1 subunit staining of interneurons also disappeared after KA treatment, suggesting acute degeneration of these cells. Likewise, GAT1 immunoreactivity revealed degenerating terminals at 24 h post-KA in CA1 and DC and subsided almost completely thereafter. Loss of CA1 and, to a lesser extent, CA3 neurons became evident at 7-15 days post-KA. It was more accentuated after 1 month, accompanied by a corresponding reduction of GABA(A)-receptor staining. In contrast, DC granule cells were markedly enlarged and dispersed in the molecular layer and exhibited a prominent increase in GABA(A)-receptor subunit staining. After 4 months, the dorsal CA1 area was lost almost entirely, CA3 was reduced, and the DG represented most of the remaining dorsal hippocampal formation. No significant morphological alterations were detected contralaterally. These results suggest that loss of hilar cells and GABAergic neurons contributes to epileptogenesis in this model of MTLE. In contrast, long-term degeneration of pyramidal cells and granule cell dispersion may reflect distinct responses to recurrent seizures. Finally, GABA(A)-receptor upregulation in the DG may represent a compensatory response persisting for several months in epileptic mice.

PSA‐NCAM‐dependent GDNF signaling limits neurodegeneration and epileptogenesis in temporal lobe epilepsy

“…A gradual dispersion of dentate gyrus granule cells that was evident after 8 days became prominent after 14 days ( Fig. 1A), as described previously (Suzuki et al, 1995;Bouilleret et al, 2000). The contralateral side remained morphologically unaffected compared with control ( Fig.…”

Loss of zolpidem efficacy in the hippocampus of mice with the GABAA receptor γ2 F77I point mutation

“…1). Immunolabelling for the GABA A receptor subunits in mice, either carrying the point mutation or in control littermates, was similar to that described previously in the rat (Zimprich et al, 1991;Gutierrez et al, 1994;Fritschy & Mohler, 1995;Sperk et al, 1997;Pirker et al, 2000) and mouse (Fritschy et al, 1998;Baer et al, 2000;Bouilleret et al, 2000;Crestani et al, 2002;Schweizer et al, 2003).…”

The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy

“…Hippocampal CR-positive cells were shown to be vulnerable to excitotoxic cell damage in ischaemia (Freund and Maglóczky, 1993) and in various models of epilepsy (Figure 6; Magloczky and Freund, 1993; Maglóczky and Freund, 1995; Ben-Ari and Cossart, 2000; Bouilleret et al, 2000; André et al, 2001; Domínguez et al, 2003; Slézia et al, 2004; van Vliet et al, 2004; Cobos et al, 2005; Tang et al, 2006; Wu et al, 2012; Huusko et al, 2013). …”

“…The different vulnerability of interneurons in temporal lobe epilepsy (TLE) was shown in numerous animal models and human patients (Babb et al, 1989; Houser, 1991; Sloviter, 1999; Ben-Ari and Cossart, 2000; Bouilleret et al, 2000; André et al, 2001; Ben-Ari, 2001; Arellano et al, 2004; Ben-Ari and Holmes, 2005; Kuruba et al, 2011; Marx et al, 2013). In most studies, the relative preservation of the inhibitory input to the perisomatic domain of principal cells was described, whereas dendritic inhibition was found to be decreased (Cossart et al, 2001; Sundstrom et al, 2001; Wittner et al, 2001, 2005; Maglóczky and Freund, 2005; Tyan et al, 2014).…”