Selective Lesioning of the Basal Forebrain Cholinergic System by Intraventricular 192 IgG–saporin: Behavioural, Biochemical and Stereological Studies in the Rat
Selective Lesioning of the Basal Forebrain Cholinergic System by Intraventricular 192 IgG–saporin: Behavioural, Biochemical and Stereological Studies in the Rat
复制标题
DOI：
10.1111/j.1460-9568.1995.tb01068.x
复制
发表时间：
1995-02
影响因子：
3.4
通讯作者：
G. Leanza;G. Leanza;O. Nilsson;R. Wiley;A. Björklund
中科院分区：
文献类型：
--
作者：
G. Leanza;G. Leanza;O. Nilsson;R. Wiley;A. Björklund
阐明基底前脑胆碱能系统的功能作用需要获得高度特异性和有效的胆碱能神经毒素。最近，在脑室内注射新引入的免疫毒素 192 IgG-皂草素后，大鼠基底前脑中携带神经生长因子 (NGF) 受体的胆碱能神经元发生选择性耗竭，相关皮质区域的胆碱能神经支配显着丧失。在此，我们扩展了这些初步发现，并报告称，将增加剂量（1.25、2.5、5.0 或 10 μg）的 192 IgG-皂素结合物注入成年大鼠的侧脑室，会引起水迷宫任务和被动回避保留的剂量依赖性损伤，但对运动活动的影响较弱且不一致。这些行为变化与海马和几个皮质区域胆碱乙酰转移酶活性的降低（高达 97%）以及隔对角带区域和大细胞基底核中 NGF 受体阳性胆碱能神经元的选择性消耗（高达 99%）并行。相比之下，隔膜中含有非胆碱能小清蛋白的神经元完全幸免，而其他胆碱能投射系统（例如纹状体、丘脑、脑干和脊髓）即使在最高剂量下也不受影响。在脑室内注射单剂量（5μg）免疫毒素后，所观察到的水迷宫和被动回避任务的变化以及胆碱能细胞损失可维持至少8个月。结果证实了 192 IgG-皂草素毒素对于基底前脑胆碱能神经元的选择性和深度损伤的有用性，并为基底前脑胆碱能系统在认知功能中的作用提供了进一步的支持。
The elucidation of the functional role of the basal forebrain cholinergic system will require access to a highly specific and efficient cholinergic neurotoxin. Recently, selective depletion of the nerve growth factor (NGF) receptor‐bearing cholinergic neurons in the rat basal forebrain and a dramatic loss of cholinergic innervation in the related cortical regions have been obtained following intraventricular injection of a newly introduced immunotoxin, 192 IgG‐saporin. Here we extend these initial findings and report that administration of increasing doses (1.25, 2.5, 5.0 or 10 μg) of the 192 IgG‐saporin conjugate into the lateral ventricles of adult rats induced dose‐dependent impairments in the water maze task and passive avoidance retention, but only weak and inconsistent effects on locomotor activity. These behavioural changes were paralleled by a reduction in choline acetyltransferase activity in hippocampus and several cortical areas (up to 97%) and selective depletions of NGF receptor‐positive cholinergic neurons in the septal‐diagonal band area and nucleus basalis magnocellularis (up to 99%). By contrast, the non‐cholinergic parvalbumin‐containing neurons in the septum were completely spared, and other cholinergic projection systems (such as in the striatum, thalamus, brainstem and spinal cord) were unaffected even at the highest dose. The observed changes in the water maze and passive avoidance tasks, as well as the cholinergic cell loss, were maintained up to at least 8 months following the intraventricular injection of a single dose (5 μg) of the immunotoxin. The results confirm the usefulness of the 192 IgG‐saporin toxin for selective and profound lesions of the basal forebrain cholinergic neurons and provide further support for a role of the basal forebrain cholinergic system in cognitive functions.