Working memory relies on the dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity relies on acetylcholine, although the molecular mechanisms for this dependence are not thoroughly understood. This study investigated the role of muscarinic M1 receptors (M1Rs) in the dlPFC using iontophoresis coupled with single-unit recordings from aging monkeys with naturally occurring cholinergic depletion. We found that M1R stimulation produced an inverted-U dose response on cell firing and behavioral performance when given systemically to aged monkeys. Immunoelectron microscopy localized KCNQ isoforms (Kv7.2, Kv7.3, and Kv7.5) on layer III dendrites and spines, similar to M1Rs. Iontophoretic manipulation of KCNQ channels altered cell firing and reversed the effects of M1R compounds, suggesting that KCNQ channels are one mechanism for M1R actions in the dlPFC. These results indicate that M1Rs may be an appropriate target to treat cognitive disorders with cholinergic alterations.

中文翻译：

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毒蕈碱型M1受体通过灵长类前额叶皮层中的KCNQ钾通道调节工作记忆性能和活性。

工作记忆依赖于背外侧前额叶皮层（dlPFC），其中锥体神经元的微电路可在没有感觉输入的情况下持续激发，并通过反复激发来维持信息。该活性依赖于乙酰胆碱，尽管对该依赖性的分子机理尚未完全了解。这项研究使用离子电渗结合衰老猴子的自然发生胆碱能耗竭的单单位记录，研究了毒蕈碱M1受体（M1Rs）在dlPFC中的作用。我们发现，当全身性给予衰老的猴子时，M1R刺激对细胞射击和行为表现产生倒U剂量反应。免疫电子显微镜将局部KCNQ亚型（Kv7.2，Kv7.3和Kv7.5）定位在第三层树突和棘上，类似于M1R。KCNQ通道的离子电渗疗法改变了细胞的放电，并逆转了M1R化合物的作用，这表明KCNQ通道是dlPFC中M1R作用的一种机制。这些结果表明，M1Rs可能是治疗胆碱能改变引起的认知障碍的合适靶标。