Induction of cortical cholinergic hypofunction and memory retention deficits through intracortical AF64A infusions.
Induction of cortical cholinergic hypofunction and memory retention deficits through intracortical AF64A infusions.
复制标题
通过皮质内 AF64A 输注诱导皮质胆碱能功能减退和记忆保留缺陷。
DOI：
10.1016/0006-8993(88)90918-3
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发表时间：
1988
期刊：
影响因子：
2.9
通讯作者：
Arendash,GW
中科院分区：
文献类型：
--
作者：
Mouton,PR;Meyer,EM;Dunn,AJ;Millard,W;Arendash,GW
乙基胆碱芥子氮丙啶离子 (AF64A) 是胆碱能神经末梢高亲和力胆碱摄取的不可逆抑制剂，脑内注射后似乎可以选择性降低突触前胆碱能标记物。为了限制 AF64A 对额顶叶 (FP) 皮质内胆碱能末端的作用，本研究利用了该药物的多部位皮质输注。经过广泛的组织学分析，选择 1 nmol AF64A/1 μl 的剂量来确定 AF64A 对乙酰胆碱酯酶 (AChE) 染色、皮质胆碱能/非胆碱能标记和被动回避行为的影响。成年大鼠右侧 FP 皮层两次注射 AF64A，注射后 10 天，同侧 FP 皮层 75% 的 AChE 染色减少，因此表明该药物在皮质中广泛扩散；观察到最小的非特异性损伤（两个输注部位的同侧 FP 皮质总计仅 4%），并且在纹状体或海马中未观察到对 AChE 染色的影响。双侧 AF64A 输注到 FP 皮层（每侧两次注射）三周后，与输注载体的对照相比，在高亲和力胆碱摄取、乙酰胆碱合成、乙酰胆碱释放和 hemicholinium-3 结合方面观察到显着的额叶皮层缺陷。然而，前皮质内的胆碱乙酰转移酶活性似乎并未受到 AF64A 输注的持续影响。皮质谷氨酸脱羧酶活性以及皮质单胺能标记物和神经肽水平也不受影响。此外，接受双侧 AF64A 输注并在两周后进行测试的动物在被动回避测试的 24 小时和 48 小时休克试验中均表现出明显的记忆保留缺陷。这些结果表明，皮质 AF64A 输注会诱导皮质内突触前标记物的特异性长期胆碱能功能减退，导致显着的长期记忆障碍。由于源自 Meynert 基底核的 FP 皮质的主要胆碱能神经支配在阿尔茨海默病中似乎变得功能障碍（但并非完全退化），因此皮质 AF64A 输注可能通过“功能性”消除皮质胆碱能末端来密切反映这种胆碱能功能障碍。
Ethylcholine mustard aziridinium ion (AF64A), an irreversible inhibitor of high-affinity choline uptake on cholinergic nerve terminals, appears to selectively decrease presynaptic cholinergic markers after intracerebral injection. To restrict AF64A's action to cholinergic terminals within the frontoparietal (FP) cortex, the present study utilized multiple-site cortical infusions of the agent. Following an extensive histological analysis, a dose of 1 nmol AF64A/1 μl was selected for determining AF64A's effects on acetylcholinesterase (AChE) staining, cortical cholinergic/non-cholinergic markers, and passive avoidance behavior. Adult rats given two infusions of AF64A into the right FP cortex had reduced AChE staining throughout 75% of the ipsilateral FP cortex at 10 days following infusion, thus suggesting an extensive cortical diffusion of the agent; minimal non-specific damage was seen (totalling only 4% of the ipsilateral FP cortex for both infusion sites) and no effects on AChE staining were observed in the striatum or hippocampus. Three weeks after bilateral AF64A infusions into the FP cortex (two injections on each side), significant frontal cortex deficits were observed in high-affinity choline uptake, acetylcholine synthesis, acetylcholine release, and hemicholinium-3 binding compared to vehicle-infused controls. However, choline acetyltransferase activity within the anterior cortex did not appear to be consistently affected by AF64A infusion. Cortical glutamic acid decarboxylase activity, as well as cortical monoaminergic markers, and neuropeptide levels were also unaffected. Moreover, animals that received bilateral AF64A infusions and were tested two weeks afterwards showed marked memory retention deficits during both the 24-h and 48-h postshock trials of passive avoidance testing. These results indicate that cortical AF64A infusion induces a specific, long-term cholinergic hypofunction of presynaptic markers within the cortex, resulting in a significant long-term memory impairment. Since the primary cholinergic innervation to the FP cortex, originating in the nucleus basalis of Meynert, appears to become dysfunctional (but not totally degenerative) in Alzheimer's disease, cortical AF64A infusions may closely reflect this cholinergic dysfunction by ‘functionally’ eliminating cortical cholinergic terminals.