title: Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.
abstract: Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ghoshal
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Dickerson
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Roop
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Morrison
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lamsal
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Noetzel
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Poslusney
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Melancon
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010622:Phencyclidine; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D012919:Social Behavior
chemical_list: D014150:Antipsychotic Agents; D011725:Pyridines; D011758:Pyrroles; D043643:Receptor, Muscarinic M1; C000610754:VU0453595; D010622:Phencyclidine