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.
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Acknowledgements
This work was supported by funding from the National Institute of Mental Health (grants U01 MH087965, R01 MH073676, 2RO1 MH082867, and U54 MH0845659). We sincerely thank James T Maksymetz for his diligent help in conducting some of the electrophysiological studies.
Author contributions
AG and JMR: designed, performed experiments, analyzed data, and wrote the article; JWD and GNR: acquired data for behavioral experiments; NJ-S, AL, and MJN: acquired data for molecular screening experiments; MSP, MRW, BJM, and SRS: performed chemical synthesis of compounds and wrote the article; RDM: acquired data for pharmacokinetic studies; JSD: supervised pharmacokinetic studies; CMN: supervised molecular studies and wrote the article; ZX: supervised electrophysiological studies and wrote the article; CKJ: supervised behavioral studies; CWL: supervised the chemistry studies and wrote the article; and PJC: supervised and designed experiments and wrote the article.
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Ghoshal, A., Rook, J., Dickerson, J. et al. Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model. Neuropsychopharmacol 41, 598–610 (2016). https://doi.org/10.1038/npp.2015.189
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DOI: https://doi.org/10.1038/npp.2015.189
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