title: Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition.
abstract: 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.
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: Feng
authors.initials: F
authors.lastname: Yi
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: Jackson
authors.initials: J
authors.lastname: Ball
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: Kurt E
authors.initials: KE
authors.lastname: Stoll
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences Neuroscience Graduate Program.
authors.forename: Vaishali C
authors.initials: VC
authors.lastname: Satpute
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences Davidson Honors College, The University of Montana, Missoula, MT 59812, USA.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Mitchell
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Pauli
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Holloway
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences.
authors.forename: April D
authors.initials: AD
authors.lastname: Johnston
authors.affiliation: Department of Pharmacology, University of Washington, Box 357750, Seattle, WA 98195-7750, USA.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Nathanson
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Howard Hughes Medical Institute, RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gerber
authors.affiliation: Howard Hughes Medical Institute, RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tonegawa
authors.affiliation: COBRE Center for Structural and Functional Neuroscience Department of Biomedical and Pharmaceutical Sciences josh.lawrence@umontana.edu.
authors.forename: J Josh
authors.initials: JJ
authors.lastname: Lawrence
mesh_terms: D000200:Action Potentials; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D003071:Cognition; D005260:Female; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D043643:Receptor, Muscarinic M1