title: Early loss of interneurons and delayed subunit-specific changes in GABA(A)-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.
authors.affiliation: lnstitute of Pharmacology, University of Zurich, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Bouilleret
authors.forename: F
authors.initials: F
authors.lastname: Loup
authors.forename: T
authors.initials: T
authors.lastname: Kiener
authors.forename: C
authors.initials: C
authors.lastname: Marescaux
authors.forename: J M
authors.initials: JM
authors.lastname: Fritschy
mesh_terms: D000818:Animals; D064092:Calbindin 1; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins / Q000378:metabolism; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology*; D007839:Functional Laterality; D050485:GABA Plasma Membrane Transport Proteins; D007150:Immunohistochemistry; D007395:Interneurons / Q000473:pathology / Q000502:physiology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D027361:Organic Anion Transporters; D010320:Parvalbumins / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors
chemical_list: C576498:CALB1 protein, human; C576764:CALB2 protein, human; C576499:Calb1 protein, mouse; C576511:Calb2 protein, mouse; D064092:Calbindin 1; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D027361:Organic Anion Transporters; D010320:Parvalbumins; D011963:Receptors, GABA-A; D064030:S100 Calcium Binding Protein G; C493413:SLC6A1 protein, human; C493414:Slc6a1 protein, mouse; D007608:Kainic Acid