Shetty Ashok K, Hattiangady Bharathi
Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina 27710, USA.
Hippocampus. 2007;17(10):943-56. doi: 10.1002/hipo.20311.
Degeneration of the CA3 pyramidal and dentate hilar neurons in the adult rat hippocampus after an intracerebroventricular kainic acid (KA) administration, a model of temporal lobe epilepsy, leads to permanent loss of the calcium binding protein calbindin in major fractions of dentate granule cells and CA1 pyramidal neurons. We hypothesize that the enduring loss of calbindin in the dentate gyrus and the CA1 subfield after CA3-lesion is due to disruption of the hippocampal circuitry leading to hyperexcitability in these regions; therefore, specific cell grafts that are capable of both reconstructing the disrupted circuitry and suppressing hyperexcitability in the injured hippocampus can restore calbindin. We compared the effects of fetal CA3 or CA1 cell grafting into the injured CA3 region of adult rats at 45 days after KA-induced injury on the hippocampal calbindin. The calbindin immunoreactivity in the dentate granule cells and the CA1 pyramidal neurons of grafted animals was evaluated at 6 months after injury (i.e. at 4.5 months post-grafting). Compared with the intact hippocampus, the calbindin in "lesion-only" hippocampus was dramatically reduced at 6 months post-lesion. However, calbindin expression was restored in the lesioned hippocampus receiving CA3 cell grafts. In contrast, in the lesioned hippocampus receiving CA1 cell grafts, calbindin expression remained less than the intact hippocampus. Thus, specific cell grafting restores the injury-induced loss of calbindin in the adult hippocampus, likely via restitution of the disrupted circuitry. Since loss of calbindin after hippocampal injury is linked to hyperexcitability, re-expression of calbindin in both dentate gyrus and CA1 subfield following CA3 cell grafting may suggest that specific cell grafting is efficacious for ameliorating injury-induced hyperexcitability in the adult hippocampus. However, electrophysiological studies of KA-lesioned hippocampus receiving CA3 cell grafts are required in future to validate this possibility.
在成年大鼠海马体中，脑室内注射红藻氨酸（KA）可导致颞叶癫痫模型中CA3锥体神经元和齿状回门区神经元变性，进而导致齿状颗粒细胞和CA1锥体神经元的主要部分中钙结合蛋白钙调蛋白永久性缺失。我们推测，CA3损伤后齿状回和CA1亚区钙调蛋白的持续缺失是由于海马回路破坏导致这些区域兴奋性过高；因此，能够重建受损回路并抑制受损海马体兴奋性过高的特定细胞移植可以恢复钙调蛋白。我们比较了在KA诱导损伤后45天，将胎儿CA3或CA1细胞移植到成年大鼠受损CA3区域对海马体钙调蛋白的影响。在损伤后6个月（即移植后4.5个月）评估移植动物齿状颗粒细胞和CA1锥体神经元中的钙调蛋白免疫反应性。与完整海马体相比，“仅损伤”海马体在损伤后6个月时钙调蛋白显著减少。然而，接受CA3细胞移植的受损海马体中钙调蛋白表达得以恢复。相比之下，在接受CA1细胞移植的受损海马体中，钙调蛋白表达仍低于完整海马体。因此，特定细胞移植可能通过恢复受损回路来恢复成年海马体中损伤诱导的钙调蛋白缺失。由于海马体损伤后钙调蛋白的缺失与兴奋性过高有关，CA3细胞移植后齿状回和CA1亚区钙调蛋白的重新表达可能表明特定细胞移植对于改善成年海马体中损伤诱导的兴奋性过高是有效的。然而，未来需要对接受CA3细胞移植的KA损伤海马体进行电生理研究以验证这种可能性。
