Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo apermanent reduction in number following kainic acid-induced degeneration of CA3 pyramidal neurons

Kainic acid (KA)-induced degeneration of CA3 pyramidal neurons leads to syn aptic reorganization and hyperexcitability in both dentate gyrus and CA1 re gion of the hippocampus. We hypothesize that the substrate for hippocampal inhibitory circuitry incurs significant and permanent alterations following degeneration of CA3 pyramidal neurons. We quantified changes in interneuro n density (N-v) in all strata of the dentate gyrus and the CA1 and CA3 subf ields of adult rats at 1, 4, and 6 months following intracerebroventricular (icv) KA administration, using glutamic acid decarboxylase-67 (GAD-67) imm unocytochemistry. At 1 month postlesion, GAD-67-positive interneuron densit y was significantly reduced in all strata of every hippocampal region excep t stratum pyramidale of CA1, The reduction in GAD-67-positive interneuron d ensity either persisted or exacerbated at 4 and 6 months postlesion in ever y stratum of all hippocampal regions. Further, the soma of remaining GAD-67 -positive interneurons in dentate gyrus and CA3 subfield showed significant hypertrophy. Thus, both permanent reductions in the density of GAD-67-posi tive interneurons in all hippocampal regions and somatic hypertrophy of rem aining GAD-67-positive interneurons in dentate gyrus and CA3 subfield occur following icy KA, In contrast, the density of interneurons visualized with Nissl in CA1 and CA3 regions was nearly equivalent to that in the intact h ippocampus at all postlesion time points. Collectively, these results sugge st that persistent reductions in GAD-67-positive interneuron density observ ed throughout the hippocampus following CA3 lesion are largely due to a per manent loss of GAD-67 expression in a significant fraction of interneurons, rather than widespread degeneration of interneurons, Nevertheless, a persi stent decrease in interneuron activity, as evidenced by permanent down-regu lation of GAD-67 in a major fraction of interneurons, would likely enhance the degree of hyperexcitability in the CA3-lesioned hippocampus. (C) 2001 A cademic Press.