Shetty A K, Turner D A
Medical Research and Surgery (Neurosurgery) Services, Duke University Medical Center, Durham, North Carolina, 27710, USA.
Exp Neurol. 1997 Feb;143(2):231-45. doi: 10.1006/exnr.1996.6363.
Selective lesion of the rat hippocampus using an intracerebroventricular administration of kainic acid (KA) represents an animal model for studying both lesion recovery and temporal lobe epilepsy. This KA lesion leads initially to loss of CA3 hippocampal neurons, the postsynaptic target of mossy fibers, and later results in aberrant mossy fiber sprouting into the dentate supragranular layer (DSGL). Because of the close association of this aberrant mossy fiber sprouting with an increase in the seizure susceptibility of the dentate gyrus, delayed therapeutic strategies capable of suppressing the sprouting of mossy fibers into the DSGL are of significant importance. We hypothesize that neural grafting can restore the disrupted hippocampal mossy fiber circuitry in this model through the establishment of appropriate mossy fiber projections onto grafted pyramidal neurons and that these appropriate projections will lead to reduced inappropriate sprouting into the DSGL. Large grafts of Embryonic Day 19 hippocampal cells were transplanted into adult hippocampus at 4 days post-KA lesion. Aberrant mossy fiber sprouting was quantified after 3-4 months survival using three different measures of Timm's staining density. Grafts located near the degenerated CA3 cell layer showed dense ingrowth of host mossy fibers compared to grafts elsewhere in the hippocampus. Aberrant mossy fiber sprouting throughout the dentate gyrus was dramatically and specifically reduced in animals with grafts near the degenerated CA3 cell layer compared to "lesion only" animals and those with ectopic grafts away from the CA3 region. These results reveal the capability of appropriately placed fetal hippocampal grafts to restore disrupted hippocampal mossy fiber circuitry by attracting sufficient host mossy fibers to suppress the development of aberrant circuitry in hippocampus. Thus, providing an appropriate postsynaptic target at early postlesion periods significantly facilitates lesion recovery. The graft-induced long-term suppression of aberrant sprouting shown here may provide a new avenue for amelioration of hyperexcitability that occurs following hippocampal lesions.
通过脑室内注射 kainic 酸（KA）对大鼠海马体进行选择性损伤，是一种用于研究损伤恢复和颞叶癫痫的动物模型。这种 KA 损伤最初会导致海马体 CA3 神经元丧失，而海马体 CA3 神经元是苔藓纤维的突触后靶点，随后会导致苔藓纤维异常发芽进入齿状回颗粒上层（DSGL）。由于这种异常的苔藓纤维发芽与齿状回癫痫易感性增加密切相关，因此能够抑制苔藓纤维向 DSGL 发芽的延迟治疗策略具有重要意义。我们假设神经移植可以通过在移植的锥体神经元上建立适当的苔藓纤维投射，来恢复该模型中受损的海马体苔藓纤维回路，并且这些适当的投射将减少向 DSGL 的不适当发芽。在 KA 损伤后 4 天，将大量胚胎第 19 天的海马体细胞移植到成年海马体中。在存活 3 - 4 个月后，使用三种不同的 Timm 染色密度测量方法对异常苔藓纤维发芽进行量化。与海马体其他部位的移植相比，位于退化的 CA3 细胞层附近的移植显示出宿主苔藓纤维的密集向内生长。与“仅损伤”动物和 CA3 区域外有异位移植的动物相比，在退化的 CA3 细胞层附近有移植的动物中，整个齿状回的异常苔藓纤维发芽显著且特异性地减少。这些结果揭示了适当放置的胎儿海马体移植通过吸引足够的宿主苔藓纤维来抑制海马体中异常回路的发展，从而恢复受损海马体苔藓纤维回路的能力。因此，在损伤后早期提供适当的突触后靶点可显著促进损伤恢复。此处显示的移植诱导的对异常发芽的长期抑制可能为改善海马体损伤后发生的过度兴奋提供一条新途径。
