1. Potentiation of the muscarinic acetylcholine receptor 1 modulates neurophysiological features in a mouse model of Rett syndrome.
- Author
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Dong HW, Weiss K, Baugh K, Meadows MJ, Niswender CM, and Neul JL
- Subjects
- Animals, Mice, Female, Mice, Inbred C57BL, Methyl-CpG-Binding Protein 2 genetics, Evoked Potentials, Auditory drug effects, Evoked Potentials, Auditory physiology, Electroencephalography methods, Male, Rett Syndrome genetics, Rett Syndrome physiopathology, Rett Syndrome drug therapy, Disease Models, Animal, Receptor, Muscarinic M1 metabolism, Receptor, Muscarinic M1 genetics
- Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2 expression after disease onset in a mouse model of RTT reverses phenotypes, providing hope for development of treatments for RTT. Translatable biomarkers of improvement and treatment responses have the potential to accelerate both preclinical and clinical evaluation of targeted therapies in RTT. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials, that correlate with disease severity, suggesting that they could be useful as biomarkers of disease improvement or early treatment response. We recently demonstrated that treatment of RTT mice with a positive allosteric modulator (PAM) of muscarinic acetylcholine subtype 1 receptor (M
1 ) improved phenotypes, suggesting that modulation of M1 activity is a potential therapy in RTT. To evaluate whether neurophysiological features could be useful biomarkers to assess the effects of M1 PAM treatment, we acutely administered the M1 PAM VU0486846 (VU846) at doses of 1, 3, 10 and 30 mg/kg in wildtype and RTT mice. This resulted in an inverted U-shaped dose response with maximal improvement of AEP features at 3 mg/kg but with no marked effect on basal EEG power or epileptiform discharges in RTT mice and no significant changes in wildtype mice. These findings suggest that M1 potentiation can improve neural circuit synchrony to auditory stimuli in RTT mice and that neurophysiological features have potential as pharmacodynamic or treatment-responsive biomarkers for preclinical and clinical evaluation of putative therapies in RTT., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey Neul reports financial support was provided by National Institute for Child Health and Development. Jeffrey Neul reports financial support was provided by International Rett Syndrome Foundation. Colleen Niswender reports financial support was provided by International Rett Syndrome Foundation. Colleen Niswender reports a relationship with ACADIA Pharmaceuticals Inc that includes: funding grants. Colleen Niswender reports a relationship with Neumora Therapeutics that includes: funding grants. Colleen Niswender received royalties from Acadia Pharmaceutical and Neumora Therapeutics for various classes of muscarinic receptor modulators. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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