Sensorimotor gating is an endophenotype of schizophrenia that is used extensively in animal models of the disease. Memory impairments are also associated with core symptoms of schizophrenia, but defining their exact relation to explicit or implicit deficits has been more elusive (Vakalopoulos, 2011). The pervasive role of muscarinic signaling in negative and positive symptoms, endophenotypes, and memory dysfunction offers a promising area of research for a nonaminergic causal chain of events in schizophrenic pathophysiology (Vakalopoulos, 2006). NMDA receptor antagonists are useful in modeling negative symptoms. NMDA dysfunction has been proposed as a proxy for core muscarinic receptor deficits in schizophrenia, especially the deficit syndrome (Vakalopoulos, 2006, 2014). The recent study by Choy et al. (2016) demonstrates the utility of such a conceptualization in guiding translational research for more effective symptom control. The selective positive allosteric modulator (PAM) of the muscarinic m1 receptor BQCA reversed both prepulse inhibition and Y-maze spatial memory deficits in mice treated with MK-801, and this was specifically m1 receptor-dependent. Familiarity-based Y-maze performance is consistent with the modulation of implicit memory traces.

The authors speculate on the potential utility of PAMs at the muscarinic receptor in augmenting conventional antipsychotic therapy, targeting cognitive and, in particular, negative symptoms. The current suite of acetylcholine-enhancing agents has not proved clinically useful owing to a high side-effect profile. This study found that BQCA was ineffective on its own in reversing the effects of MK-801 in either paradigm. The main purpose of this letter is to explore the possible reason for this lack of effectiveness given the proposal of a primary muscarinic signaling dysfunction. If the NMDA receptor manifests critical convergent intracellular cascades, then it is likely to affect multiple muscarinic receptor subtypes. Thus, an inverse model of monoamine-muscarinic signaling (Vakalopoulos, 2006) could account for enhancement by unmasking broader muscarinic function with subthreshold doses of both atypical and typical neuroleptics. This concept is supported by the effect of the acetylcholinesterase inhibitor galantamine, but not donepezil, in reversing PPI deficits induced by MK-801 in rats (Hohnadel et al., 2007). Interestingly, another potent and highly selective PAM at m1 mitigated deficits in novel object recognition and cued fear conditioning associated with a mouse NR1 subunit of NMDA knockdown (Grannan et al., 2016). No neuroleptics were required, but 10%–15% of wild-type function is preserved in this knockdown.

In summary, research on PAMs of muscarinic receptors is certainly a game-changer in developing a new approach to therapeutics for schizophrenia and facilitating a more profound understanding of the essential nature of the disease.

• Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics