Optimized Administration of the M PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mice. Journal Article

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Authors: Cikowski, J; Holt, C; Arthur, B; Smith, M; Gonzalez, S; Lindsley, CW; Niswender, CM; Gogliotti, RG
Article Title: Optimized Administration of the M PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mice.
Abstract: Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of in cholinergic neurons evokes the same social and cognitive phenotypes in mice seen with global knockout, and decreased choline acetyltransferase activity and vesamicol binding have been reported in RTT autopsy samples. Further, we recently identified significant decreases in muscarinic acetylcholine receptor subtype 4 (M) expression in both the motor cortex and cerebellum of RTT patient autopsies and established proof of concept that an acute dose of the positive allosteric modulator (PAM) VU0467154 (VU154) rescued phenotypes in mice. Here, we expand the assessment of M PAMs in RTT to address clinically relevant questions of tolerance, scope of benefit, dose response, chronic treatment, and mechanism. We show that VU154 has efficacy on anxiety, social preference, cognitive, and respiratory phenotypes in mice; however, the therapeutic range is narrow, with benefits seen at 3 mg/kg concentrations, but not 1 or 10 mg/kg. Further, sociability was diminished in VU154-treated mice, suggestive of a potential adverse effect. Compound efficacy on social, cognitive, and respiratory phenotypes was conserved with a 44-day treatment paradigm, with the caveat that breath rate was moderately decreased with chronic treatment in and mice. VU154 effects on respiratory function correlated with an increase in Gsk3ß inhibition in the brainstem. These results identify the core symptom domains where efficacy and adverse effects may present with M administration in RTT model mice and advocate for the continued evaluation as potential RTT therapeutics.
Journal Title: ACS chemical neuroscience
Publisher: Unknown  
Date Published: 2022