Early loss of interneurons and delayed subunit-specific changes in GABA(A)-receptor expression in a mouse model of mesial temporal lobe epilepsy.

Jul 21, 2000Hippocampus

Early loss of inhibitory brain cells and later changes in specific GABA(A) receptor parts in a mouse model of temporal lobe epilepsy

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Abstract

Unilateral injection of kainic acid into the dorsal hippocampus of adult mice leads to significant changes in GABAergic neurotransmission over a period of 4 months.

Kainic acid injection causes a profound loss of hilar cells and limited damage to CA1 and CA3 pyramidal cells.
Parvalbumin and calbindin-D28k staining of interneurons disappears irreversibly in CA1 and the dentate gyrus, while calretinin staining remains intact.
Degeneration of GABA(A)-receptor alpha1 subunit staining in interneurons suggests acute cell loss following kainic acid treatment.
Loss of CA1 neurons is observed from 7-15 days post-injection and becomes more pronounced after 1 month.
Granule cells in the dentate gyrus show enlargement and increased GABA(A)-receptor subunit staining after kainic acid treatment.
After 4 months, the dorsal CA1 area is nearly entirely lost, while the dentate gyrus remains the most intact part of the dorsal hippocampal formation.

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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.

Early loss of interneurons and delayed subunit-specific changes in GABA(A)-receptor expression in a mouse model of mesial temporal lobe epilepsy.

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