Expression of GABA_A receptor subunits in the hippocampus of the rat after kainic acid-induced seizures

Abstract 

The GABA_A receptor is a ligand gated chloride channel consisting of five membrane spanning proteins for which 13 different genes have been identified in the mammalian brain. The present review summarizes recent work from our laboratory on the characterization of the immunocytochemical distribution of these GABA_A receptor subunits in the rat brain and changes in immunoreactivity and mRNA expression after kainic acid-induced status epilepticus. A heterogeneous distribution of immunoreactive GABA_A receptor subunits was observed. The most abundant ones were: α₁, α₂, α₄, α₅, β₂, β₃, γ₂ and δ. α₁, β₂, and γ₂ were about equally distributed in all subfields of the hippocampus; α₄- and δ-subunits were preferentially found in the dentate molecular layer and in CA1; α₂ was localized to the dentate molecular layer and CA3; α₅ was found in the dendritic areas of CA1 to CA3; and β₁ was preferentially seen in CA2. α₁, β₂, γ₂ and δ were highly concentrated in interneurons. Kainic acid-induced seizures caused acute and chronic changes in the expression of mRNAs and immunoreactive proteins. Acute changes included decreases in α₂, α₅, β₁, β₃, γ₂ and δ mRNA levels (by about 25–50%), accompanied by increases (by about 50%) in α₁, α₄, and β₂ messages in granule cells (after 6–12 h). Chronic changes, characterized by losses in mRNA and immunoreactive proteins in CA1 and CA3, are undoubtedly due to seizure-related cell damage. However, compensatory expression of α₂ and β₃ subunits, especially in CA3b/c, was observed. Furthermore, increases in mRNAs and immunoreactive proteins were seen for α₁, α₂, α₄, β_1, β₂, β₃ and γ₂ in granule cells and in the molecular layer of the dentate gyrus at 7–30 days after kainic acid injection. The changes in the expression of GABA_A receptor subunits, observed in practically all hippocampal subfields, may reflect altered GABA-ergic transmission during development of the epileptic syndrome. Increased expression of GABA_A receptor subunits in the dendritic field of granule cells and CA3 suggest that GABA-ergic inhibition may be augmented at these levels. However, the lasting preservation of α₁-, β₂-, and γ₂-subunits in interneurons could provide a basis for augmented inhibition of GABA-ergic interneurons, leading to net disinhibition.

Keywords:  Benzodiazepines, Dentate gyrus, Limbic system, Mossy fibers, Receptor adaptation, Temporal lobe epilepsy