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.

GABA A Receptors Are Well Preserved in the Hippocampus of Aged Mice

“…In agreement with our findings, in the mouse and rat hippocampus α2 subunit expression has also been reported to show a relatively strong immunoreactivity in the pyramidal layer, particularly abundant in the axon initial segment, and strong diffuse staining in other layers of the CA1 and CA3 regions (Fritschy and Mohler, 1995; Nusser et al, 1996; Fritschy et al, 1998; Bouilleret et al, 2000). The decreased expression of α2 subunit around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions is not due to cell loss because the number of pyramidal neurons did not change as it has been revealed by the nuclear marker and the staining that was weaker but still clearly outlined the pyramidal cell bodies and dendritic processes.…”

GABA A Receptors Are Well Preserved in the Hippocampus of Aged Mice

“…In agreement with our findings, in the mouse and rat hippocampus α2 subunit expression has also been reported to show a relatively strong immunoreactivity in the pyramidal layer, particularly abundant in the axon initial segment, and strong diffuse staining in other layers of the CA1 and CA3 regions (Fritschy and Mohler, 1995; Nusser et al, 1996; Fritschy et al, 1998; Bouilleret et al, 2000). The decreased expression of α2 subunit around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions is not due to cell loss because the number of pyramidal neurons did not change as it has been revealed by the nuclear marker and the staining that was weaker but still clearly outlined the pyramidal cell bodies and dendritic processes.…”

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.…”

Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy

“…The main findings of this study support the conclusion that suppression of spontaneous activity of hippocampal neurons with reduced KCC2 expression and a high Cl − equilibrium potential elicits TLE histopathological characteristics, in terms of elevated Glu/GABA ratios of synaptic input, reduced dendrite length and elevated susceptibility of hippocampal neurons to excitotoxicity [1, 2, 42, 43]. Accordingly, our study revealed elevated expression of high‐affinity type GlyR 2 and 3 in hippocampectomies of TLE patients with a severe course of disease, according to the Wyler classification [21] of hippocampal sclerosis or the frequency of SGTCS.…”

GABA A Receptors Are Well Preserved in the Hippocampus of Aged Mice

“…In agreement with our findings, in the mouse and rat hippocampus α2 subunit expression has also been reported to show a relatively strong immunoreactivity in the pyramidal layer, particularly abundant in the axon initial segment, and strong diffuse staining in other layers of the CA1 and CA3 regions (Fritschy and Mohler, 1995; Nusser et al, 1996; Fritschy et al, 1998; Bouilleret et al, 2000). The decreased expression of α2 subunit around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions is not due to cell loss because the number of pyramidal neurons did not change as it has been revealed by the nuclear marker and the staining that was weaker but still clearly outlined the pyramidal cell bodies and dendritic processes.…”

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.…”

Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy

“…The main findings of this study support the conclusion that suppression of spontaneous activity of hippocampal neurons with reduced KCC2 expression and a high Cl − equilibrium potential elicits TLE histopathological characteristics, in terms of elevated Glu/GABA ratios of synaptic input, reduced dendrite length and elevated susceptibility of hippocampal neurons to excitotoxicity [1, 2, 42, 43]. Accordingly, our study revealed elevated expression of high‐affinity type GlyR 2 and 3 in hippocampectomies of TLE patients with a severe course of disease, according to the Wyler classification [21] of hippocampal sclerosis or the frequency of SGTCS.…”

GABA A Receptors Are Well Preserved in the Hippocampus of Aged Mice

“…In agreement with our findings, in the mouse and rat hippocampus α2 subunit expression has also been reported to show a relatively strong immunoreactivity in the pyramidal layer, particularly abundant in the axon initial segment, and strong diffuse staining in other layers of the CA1 and CA3 regions (Fritschy and Mohler, 1995; Nusser et al, 1996; Fritschy et al, 1998; Bouilleret et al, 2000). The decreased expression of α2 subunit around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions is not due to cell loss because the number of pyramidal neurons did not change as it has been revealed by the nuclear marker and the staining that was weaker but still clearly outlined the pyramidal cell bodies and dendritic processes.…”

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.…”

Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy

“…The main findings of this study support the conclusion that suppression of spontaneous activity of hippocampal neurons with reduced KCC2 expression and a high Cl − equilibrium potential elicits TLE histopathological characteristics, in terms of elevated Glu/GABA ratios of synaptic input, reduced dendrite length and elevated susceptibility of hippocampal neurons to excitotoxicity [1, 2, 42, 43]. Accordingly, our study revealed elevated expression of high‐affinity type GlyR 2 and 3 in hippocampectomies of TLE patients with a severe course of disease, according to the Wyler classification [21] of hippocampal sclerosis or the frequency of SGTCS.…”