Alreja M, Wu M, Liu W, Atkins J B, Leranth C, Shanabrough M
Departments of Psychiatry, Neurobiology, and Obstetrics and Gynecology, Yale University School of Medicine New Haven, Connecticut 06508, USA.
J Neurosci. 2000 Nov 1;20(21):8103-10. doi: 10.1523/JNEUROSCI.20-21-08103.2000.
Systemic infusions of the muscarinic cholinergic receptor antagonists atropine and scopolamine (atr/scop) produce an amnesic syndrome in humans, subhuman primates, and rodents. In humans, this syndrome may resemble early symptoms of Alzheimer's disease. Behavioral studies in rats have demonstrated that the medial septum/diagonal band of Broca (MSDB), which sends cholinergic and GABAergic projections to the hippocampus, is a critical locus in mediating the amnesic effects of atr/scop. The amnesic effects of atr/scop in the MSDB have been presumed but not proven to be caused by a decrease in hippocampal acetylcholine (ACh) release after blockade of a muscarinic tone in the MSDB. Using electrophysiological recordings and fluorescent-labeling techniques to identify living septohippocampal neurons in rat brain slices, we now report that, contrary to current belief, a blockade of the muscarinic tone in the MSDB does not decrease impulse flow in the septohippocampal cholinergic pathway; instead, it decreases impulse flow in the septohippocampal GABAergic pathway via M(3) muscarinic receptors. We also report that the muscarinic tone in the MSDB is maintained by ACh that is released locally, presumably via axon collaterals of septohippocampal cholinergic neurons. As such, cognitive deficits that occur in various neurodegenerative disorders that are associated with a loss or atrophy of septohippocampal cholinergic neurons cannot be attributed solely to a decrease in hippocampal acetylcholine release. An additional, possibly more important mechanism may be the concomitant decrease in septohippocampal GABA release and a subsequent disruption in disinhibitory mechanisms in the hippocampus. Restoration of impulse flow in the septohippocampal GABA pathway, possibly via M(3) receptor agonists, may, therefore, be critical for successful treatment of cognitive deficits associated with neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
向人体、非人灵长类动物和啮齿动物全身输注毒蕈碱胆碱能受体拮抗剂阿托品和东莨菪碱（阿托品/东莨菪碱）会导致失忆综合征。在人类中，这种综合征可能类似于阿尔茨海默病的早期症状。对大鼠的行为研究表明，向海马体发送胆碱能和γ-氨基丁酸能投射的内侧隔区/布罗卡斜带（MSDB）是介导阿托品/东莨菪碱失忆效应的关键部位。阿托品/东莨菪碱在MSDB中的失忆效应被推测但尚未被证实是由于MSDB中毒蕈碱张力被阻断后海马乙酰胆碱（ACh）释放减少所致。我们使用电生理记录和荧光标记技术来识别大鼠脑片中存活的隔海马神经元，现在报告，与目前的看法相反，MSDB中毒蕈碱张力的阻断不会减少隔海马胆碱能通路中的冲动流；相反，它通过M(3)毒蕈碱受体减少隔海马γ-氨基丁酸能通路中的冲动流。我们还报告，MSDB中的毒蕈碱张力由局部释放的ACh维持，推测是通过隔海马胆碱能神经元的轴突侧支释放的。因此，与隔海马胆碱能神经元丧失或萎缩相关的各种神经退行性疾病中出现的认知缺陷不能仅仅归因于海马乙酰胆碱释放的减少。另一种可能更重要的机制可能是隔海马γ-氨基丁酸释放的同时减少以及随后海马中去抑制机制的破坏。因此，可能通过M(3)受体激动剂恢复隔海马γ-氨基丁酸通路中的冲动流，对于成功治疗与阿尔茨海默病和帕金森病等神经退行性疾病相关的认知缺陷可能至关重要。
