Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: Roles in cellular excitability, inhibitory transmission and cognition

摘要

Parvalbumin-containing (PV) neurons from mouse CA1 hippocampus (HC) and prefrontal cortex exhibit a fast spiking phenotype in vitro. Within CA1, HC PV cells are mainly comprised of basket and bistratified cell types. Direct activation of muscarinic acetylcholine receptors (mAChRs) enhances excitability more in CA1 HC than in prefrontal cortex PV cells. mAChR-induced excitation of CA1 PV cells occurs through direct activation of M1 mAChRs. Transgenetic deletion of M1 mAChRs from PV cells diminishes M1 mAChR expression and cholinergic excitation of CA1 PV cells. mAChR-induced excitation exclusively in PV cells enhances GABAergic transmission in CA1 pyramidal cells. In vivo activation of M1 mAChRs in PV cells is important in recognition and working memory but not spatial memory. 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.