Yi Feng, Ball Jackson, Stoll Kurt E, Satpute Vaishali C, Mitchell Samantha M, Pauli Jordan L, Holloway Benjamin B, Johnston April D, Nathanson Neil M, Deisseroth Karl, Gerber David J, Tonegawa Susumu, Lawrence J Josh
COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences Neuroscience Graduate Program.
J Physiol. 2014 Aug 15;592(16):3463-94. doi: 10.1113/jphysiol.2014.275453. Epub 2014 May 30.
Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M1 mAChRs genetically from PV interneurons, we created PV-M1 knockout mice by crossing PV-CRE and floxed M1 mice. The elimination of M1 mAChRs from PV cells diminished M1 mAChR immunoreactivity and muscarinic excitation of HC PV cells. Selective cholinergic activation of HC PV interneurons using Designer Receptors Exclusively Activated by Designer Drugs technology enhanced the frequency and amplitude of inhibitory synaptic currents in CA1 pyramidal cells. Finally, relative to wild-type controls, PV-M1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M1 mAChRs on PV cells contributes to some forms of learning and memory.
含小白蛋白（PV）的神经元是γ-氨基丁酸能中间神经元的主要类型，是学习网络的重要电路元件。在主动学习任务中，随着乙酰胆碱水平的升高，PV神经元越来越多地参与网络动态。相反，胆碱能或PV中间神经元功能的损害会导致学习缺陷。在这里，我们研究了海马体（HC）和前额叶皮质（PFC）中的PV中间神经元及其受毒蕈碱型乙酰胆碱受体（mAChRs）的调节。通过将PV-CRE小鼠与Rosa26YFP小鼠杂交可视化的HC PV细胞，在解剖学上被鉴定为锥体层中的篮状细胞和PV双分层细胞；在海马体的下托层，HC PV细胞在电生理上与含生长抑素的细胞不同。在药理学上阻断谷氨酸能传递后，mAChR激活增强了CA1区HC和PFC中PV细胞的兴奋性；然而，CA1区HC PV细胞表现出比PFC PV细胞更强的突触后去极化。为了从PV中间神经元中基因删除M1 mAChRs，我们通过将PV-CRE和floxed M1小鼠杂交创建了PV-M1基因敲除小鼠。从PV细胞中消除M1 mAChRs减少了M1 mAChR免疫反应性和HC PV细胞的毒蕈碱激发。使用仅由设计药物激活的设计受体技术对HC PV中间神经元进行选择性胆碱能激活，增强了CA1锥体细胞中抑制性突触电流的频率和幅度。最后，相对于野生型对照，PV-M1基因敲除小鼠表现出新颖物体识别受损，在较小程度上空间工作记忆受损，但参考记忆保持完整。因此，PV细胞上M1 mAChRs的直接激活有助于某些形式的学习和记忆。
