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Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a
A Ghoshal1, J M Rook1, J W Dickerson1
1Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
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.
Insights
Deficits in M1 muscarinic acetylcholine receptors (mAChR) are linked to schizophrenia. A novel M1 positive allosteric modulator (PAM) restored synaptic function and cognitive deficits in a mouse model, offering a potential new treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Schizophrenia is associated with M1 muscarinic acetylcholine receptor (mAChR) signaling deficits in the prefrontal cortex (PFC).
- Impaired cortical long-term depression (LTD) is a hallmark of schizophrenia.
- Phencyclidine (PCP) administration in mice serves as a model for schizophrenia-related cognitive and synaptic deficits.
Purpose of the Study:
- To investigate the role of M1 mAChR activation in inducing cortical LTD.
- To evaluate the therapeutic potential of a novel M1 positive allosteric modulator (PAM) in a PCP-induced mouse model of schizophrenia.
Main Methods:
- Selective M1 mAChR activation was used to induce LTD in the PFC.
- PCP was administered to mice to model schizophrenia.
- A novel M1 PAM, VU0453595, was administered systemically.
- LTD, cognitive function, and social interaction were assessed in PCP-treated mice.
Main Results:
- Selective M1 mAChR activation induced LTD in the PFC.
- PCP treatment abolished the M1 mAChR-induced LTD.
- VU0453595 fully restored impaired LTD in PCP-treated mice.
- VU0453595 ameliorated cognitive and social interaction deficits in PCP-treated mice.
Conclusions:
- M1 mAChR signaling is crucial for cortical LTD and cognitive function.
- Selective M1 PAMs, like VU0453595, show promise for treating schizophrenia.
- Targeting M1 mAChRs represents a novel therapeutic strategy for schizophrenia.
