{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:15:06Z","timestamp":1768511706770,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,17]]},"group-title":"Neuroscience","reference-count":42,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the\n                  <jats:italic>methyl-CpG binding protein 2<\/jats:italic>\n                  (\n                  <jats:italic>MeCP2<\/jats:italic>\n                  ) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M\n                  <jats:sub>1<\/jats:sub>\n                  muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M\n                  <jats:sub>1<\/jats:sub>\n                  receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M\n                  <jats:sub>1<\/jats:sub>\n                  is found on cholinergic interneurons, we hypothesized that M\n                  <jats:sub>1<\/jats:sub>\n                  -potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this,\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>+\/-<\/jats:italic>\n                  <\/jats:sup>\n                  and\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>+\/+<\/jats:italic>\n                  <\/jats:sup>\n                  mice were screened for apneas before and after administration of the M\n                  <jats:sub>1<\/jats:sub>\n                  positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595\u2019s efficacy on apneas. The vehicle-treated\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>+\/-<\/jats:italic>\n                  <\/jats:sup>\n                  brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that\n                  <jats:italic>Mecp2<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>+\/-<\/jats:italic>\n                  <\/jats:sup>\n                  mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M\n                  <jats:sub>1<\/jats:sub>\n                  potentiation.\n                <\/jats:p>","DOI":"10.1101\/2024.04.15.586099","type":"posted-content","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T19:23:00Z","timestamp":1713381780000},"source":"Crossref","is-referenced-by-count":1,"title":["Potentiation of the M\n                  <sub>1<\/sub>\n                  muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in\n                  <i>Mecp2<\/i>\n                  <sup>+\/-<\/sup>\n                  mice"],"prefix":"10.64898","author":[{"given":"Mackenzie","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace E.","family":"Dodis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda M.","family":"Vanderplow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yewon","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocco G.","family":"Gogliotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024042008350971000_2024.04.15.586099v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1012104107"},{"key":"2024042008350971000_2024.04.15.586099v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"2024042008350971000_2024.04.15.586099v1.3","doi-asserted-by":"crossref","first-page":"8529","DOI":"10.1038\/s41598-023-35516-7","article-title":"Respiration organizes gamma synchrony in the prefronto-thalamic network","volume":"13","year":"2023","journal-title":"Sci Rep"},{"key":"2024042008350971000_2024.04.15.586099v1.4","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000203157.31924.4a"},{"key":"2024042008350971000_2024.04.15.586099v1.5","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1997.00550160091022"},{"key":"2024042008350971000_2024.04.15.586099v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature09582"},{"key":"2024042008350971000_2024.04.15.586099v1.7","doi-asserted-by":"crossref","first-page":"1048278","DOI":"10.3389\/fnins.2023.1048278","article-title":"Cardiac autonomic control in Rett syndrome: Insights from heart rate variability analysis","volume":"17","year":"2023","journal-title":"Front Neurosci"},{"key":"2024042008350971000_2024.04.15.586099v1.8","doi-asserted-by":"crossref","first-page":"e0127082","DOI":"10.1371\/journal.pone.0127082","article-title":"Slow Breathing and Hypoxic Challenge: Cardiorespiratory Consequences and Their Central Neural Substrates","volume":"10","year":"2015","journal-title":"PLoS ONE"},{"key":"2024042008350971000_2024.04.15.586099v1.9","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6808293"},{"key":"2024042008350971000_2024.04.15.586099v1.10","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58613"},{"key":"2024042008350971000_2024.04.15.586099v1.11","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/cne.20738","article-title":"Prefrontal cortex in the rat: Projections to subcortical autonomic, motor, and limbic centers","volume":"492","year":"2005","journal-title":"J of Comparative Neurology"},{"key":"2024042008350971000_2024.04.15.586099v1.12","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.246991"},{"key":"2024042008350971000_2024.04.15.586099v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aai7459"},{"key":"2024042008350971000_2024.04.15.586099v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/mrdd.10020"},{"key":"2024042008350971000_2024.04.15.586099v1.15","doi-asserted-by":"crossref","unstructured":"Howell CJ , Sceniak MP , Lang M , Krakowiecki W , Abouelsoud FE , Lad SU , Yu H , Katz DM (2017) Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome. eNeuro 4:ENEURO.0277-17.2017.","DOI":"10.1523\/ENEURO.0277-17.2017"},{"key":"2024042008350971000_2024.04.15.586099v1.16","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-12-2-118"},{"key":"2024042008350971000_2024.04.15.586099v1.17","doi-asserted-by":"crossref","first-page":"108214","DOI":"10.1016\/j.neuropharm.2020.108214","article-title":"The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release","volume":"176","year":"2020","journal-title":"Neuropharmacology"},{"key":"2024042008350971000_2024.04.15.586099v1.18","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1242\/dmm.011007","article-title":"Preclinical research in Rett syndrome: setting the foundation for translational success","volume":"5","year":"2012","journal-title":"Disease Models & Mechanisms"},{"key":"2024042008350971000_2024.04.15.586099v1.19","doi-asserted-by":"crossref","unstructured":"Kim S-Y , Cho JH , Murray E , Bakh N , Choi H , Ohn K , Ruelas L , Hubbert A , McCue M , Vassallo SL , Keller PJ , Chung K (2015) Stochastic electrotransport selectively enhances the transport of highly electromobile molecules. Proc Natl Acad Sci USA 112 Available at: https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1510133112 [Accessed September 1, 2023].","DOI":"10.1073\/pnas.1510133112"},{"key":"2024042008350971000_2024.04.15.586099v1.20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2159-12.2012"},{"key":"2024042008350971000_2024.04.15.586099v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.11.018"},{"key":"2024042008350971000_2024.04.15.586099v1.22","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-05-04077.1995"},{"key":"2024042008350971000_2024.04.15.586099v1.23","doi-asserted-by":"crossref","unstructured":"Li W , Xu X , Pozzo-Miller L (2016) Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors. Proc Natl Acad Sci USA 113 Available at: https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1517244113 [Accessed December 20, 2023].","DOI":"10.1073\/pnas.1517244113"},{"key":"2024042008350971000_2024.04.15.586099v1.24","doi-asserted-by":"crossref","first-page":"L941","DOI":"10.1152\/ajplung.1995.268.6.L941","article-title":"Muscarinic receptor subtypes are differentially distributed across brain stem respiratory nuclei","volume":"268","year":"1995","journal-title":"American Journal of Physiology-Lung Cellular and Molecular Physiology"},{"key":"2024042008350971000_2024.04.15.586099v1.25","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.51.247"},{"key":"2024042008350971000_2024.04.15.586099v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.025"},{"key":"2024042008350971000_2024.04.15.586099v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4281"},{"key":"2024042008350971000_2024.04.15.586099v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4066"},{"key":"2024042008350971000_2024.04.15.586099v1.29","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2951-12.2012"},{"key":"2024042008350971000_2024.04.15.586099v1.30","doi-asserted-by":"crossref","unstructured":"Rusted JM , Warburton DM (1988) The effects of scopolamine on working memory in healthy young volunteers. Psychopharmacology 96 Available at: http:\/\/link.springer.com\/10.1007\/BF00177553 [Accessed March 21, 2024].","DOI":"10.1007\/BF00177553"},{"key":"2024042008350971000_2024.04.15.586099v1.31","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/s41398-022-02254-9","article-title":"Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study","volume":"12","year":"2022","journal-title":"Transl Psychiatry"},{"key":"2024042008350971000_2024.04.15.586099v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/nature14600"},{"key":"2024042008350971000_2024.04.15.586099v1.33","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1007\/s13311-022-01254-3","article-title":"Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome","volume":"19","year":"2022","journal-title":"Neurotherapeutics"},{"key":"2024042008350971000_2024.04.15.586099v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2015.06.003"},{"key":"2024042008350971000_2024.04.15.586099v1.35","doi-asserted-by":"crossref","unstructured":"Teune TM , Van Der Burg J , Van Der Moer J , Voogd J , Ruigrok TJH (2000) Topography of cerebellar nuclear projections to the brain stem in the rat. In: Progress in Brain Research, pp 141\u2013172. Elsevier. Available at: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0079612300240144 [Accessed October 24, 2023].","DOI":"10.1016\/S0079-6123(00)24014-4"},{"key":"2024042008350971000_2024.04.15.586099v1.36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14198"},{"key":"2024042008350971000_2024.04.15.586099v1.37","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s00335-019-09793-5","article-title":"Treating Rett syndrome: from mouse models to human therapies","volume":"30","year":"2019","journal-title":"Mamm Genome"},{"key":"2024042008350971000_2024.04.15.586099v1.38","doi-asserted-by":"crossref","first-page":"593554","DOI":"10.3389\/fneur.2020.593554","article-title":"Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia","volume":"11","year":"2020","journal-title":"Front Neurol"},{"key":"2024042008350971000_2024.04.15.586099v1.39","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20866"},{"key":"2024042008350971000_2024.04.15.586099v1.40","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000238302.84552.d0"},{"key":"2024042008350971000_2024.04.15.586099v1.41","doi-asserted-by":"crossref","first-page":"8082","DOI":"10.1002\/jcp.30462","article-title":"In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model","volume":"236","year":"2021","journal-title":"Journal Cellular Physiology"},{"key":"2024042008350971000_2024.04.15.586099v1.42","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20389"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.04.15.586099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:17:55Z","timestamp":1768457875000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.04.15.586099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,17]]},"references-count":42,"URL":"https:\/\/doi.org\/10.1101\/2024.04.15.586099","relation":{},"subject":[],"published":{"date-parts":[[2024,4,17]]},"subtype":"preprint"}}