Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo a permanent reduction in number following kainic acid-induced degeneration of ca3 pyramidal neurons.
Kainic acid (KA)-induced degeneration of CA3 pyramidal neurons leads to synaptic reorganization and hyperexcitability in both dentate gyrus and CA1 region 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 interneuron density (N(v)) in all strata of the dentate gyrus and the CA1 and CA3 subfields of adult rats at 1, 4, and 6 months following intracerebroventricular (icv) KA administration, using glutamic acid decarboxylase-67 (GAD-67) immunocytochemistry. At 1 month postlesion, GAD-67-positive interneuron density was significantly reduced in all strata of every hippocampal region except stratum pyramidale of CA1. The reduction in GAD-67-positive interneuron density either persisted or exacerbated at 4 and 6 months postlesion in every 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-positive interneurons in all hippocampal regions and somatic hypertrophy of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield occur following icv KA. In contrast, the density of interneurons visualized with Nissl in CA1 and CA3 regions was nearly equivalent to that in the intact hippocampus at all postlesion time points. Collectively, these results suggest that persistent reductions in GAD-67-positive interneuron density observed throughout the hippocampus following CA3 lesion are largely due to a permanent loss of GAD-67 expression in a significant fraction of interneurons, rather than widespread degeneration of interneurons. Nevertheless, a persistent decrease in interneuron activity, as evidenced by permanent down-regulation of GAD-67 in a major fraction of interneurons, would likely enhance the degree of hyperexcitability in the CA3-lesioned hippocampus.
Shetty
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AK
Departments of Surgery (Neurosurgery) and Neurobiology, Division of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA. Ashok.Shetty@Duke.Edu
Turner
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DA
D000818:Animals; D002470:Cell Survival; D018891:Dentate Gyrus / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism*; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D007608:Kainic Acid