Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities

Murasawa, Hiroyasu; Kobayashi, Hiroyuki; Imai, Jun; Nagase, Takahiko; Soumiya, Hitomi; Fukumitsu, Hidefumi

doi:10.1371/journal.pone.0258830

Cited by 6 publications

(6 citation statements)

References 78 publications

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“…In RTT autopsy samples, both decreased choline acetyltransferase (ChAT) activity and radiolabeled vesamicol binding have been reported in the putamen and in the thalamus [ 10 , 11 ]. Similar results are also observed in Mecp2 +/- rats, where decreased acetylcholine levels are observed at symptomatic ages while all other neurotransmitters remain unaffected [ 12 ]. Data from RTT mouse models agree with these findings, as loss of Mecp2 in cholinergic neurons evokes comparable anxiety, motor, social, cognitive, and cardiac phenotypes to what is observed with global Mecp2 knockout [ 13 – 15 ].…”

Section: Introductionsupporting

confidence: 80%

Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome

et al. 2022

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SummaryRett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M1, M2, M3, and M5 mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M1 expression demonstrated a linear relationship with MeCP2 expression, such that M1 levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M1 potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2+/- mice. VU595’s efficacy on apneas in Mecp2+/- mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M1 PAMs could represent a new class of RTT therapeutics.

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Section: Introductionsupporting

confidence: 80%

Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome

et al. 2022

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“…Postmortem RTT brain tissues show fewer cholinergic cells, reduced choline acetyltransferase (ChAT) activity, and decreased cholinergic receptor expression (Wenk and Mobley, 1996;Wenk, 1997;Wenk and Hauss-Wegrzyniak, 1999;Brašić et al, 2012). Mecp2 mutant animals also show reduced acetylcholine (ACh) and ChAT activity in the hippocampus, amygdala, striatum, thalamus, basal forebrain, and LC (Ricceri et al, 2011;Oginsky et al, 2014;Leung et al, 2017;Zhou et al, 2017;Murasawa et al, 2021). In Mecp2 KO mice (Bird line), currents mediated by nicotinic ACh receptors (nAChRs) are smaller in LC neurons (Oginsky et al, 2014).…”

Section: Cholinergic Activitymentioning

confidence: 99%

Excitation and Inhibition Imbalance in Rett Syndrome

2022

Front. Neurosci.

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A loss of the excitation/inhibition (E/I) balance in the neural circuit has emerged as a common neuropathological feature in many neurodevelopmental disorders. Rett syndrome (RTT), a prevalent neurodevelopmental disorder that affects 1:10,000–15,000 women globally, is caused by loss-of-function mutations in the Methyl-CpG-binding Protein-2 (Mecp2) gene. E/I imbalance is recognized as the leading cellular and synaptic hallmark that is fundamental to diverse RTT neurological symptoms, including stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions. E/I balance in RTT is not homogeneously altered but demonstrates brain region and cell type specificity instead. In this review, I elaborate on the current understanding of the loss of E/I balance in a range of brain areas at molecular and cellular levels. I further describe how the underlying cellular mechanisms contribute to the disturbance of the proper E/I ratio. Last, I discuss current pharmacologic innervations for RTT and their role in modifying the E/I balance.

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“…Indeed, loss of MeCP2 protein, specifically in cholinergic neurons, has been shown to be a strong driver of Rett-like phenotypes, such as learning deficits 46 and seizure susceptibility. 34 Moreover, decreased levels of acetylcholine have been reported in multiple brain regions of female MeCP2 -deficient gene knockout rats, 47 suggesting how cholinergic neuron activity might be substantially decreased in Rett syndrome models. Taken together, these findings suggest that MeCP2 is critical for the normal development, phenotypic maintenance and function of cholinergic neurons and, as a consequence, MeCP2-driven dysfunction of cholinergic neurons can contribute to numerous clinically relevant phenotypic aspects of Rett syndrome.…”

Section: Discussionmentioning

confidence: 99%

Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome

Tiberi,

Borgonovo,

Testa

et al. 2023

Brain

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Rett syndrome is a rare genetic neurodevelopmental disease, affecting 1 in over 10,000 females born worldwide, caused by de novo mutations in the X-chromosome-located methyl-CpG-binding protein 2 (MeCP2) gene. Despite the great effort put forth by the scientific community, a therapy for this devastating disease is still needed. Here, we tested the therapeutic effects of a painless mutein of the Nerve Growth Factor, called human NGF painless (hNGFp), via a non-invasive intranasal delivery in female MeCP2+/- mice. Of note, previous work had demonstrated a broad biodistribution of hNGFp in the mouse brain by the nasal delivery route. We report that (1) the long-term lifelong treatment of MeCP2+/- mice with hNGFp, starting at 2 months of age, increased the chance of survival while also greatly improving behavioral parameters. Furthermore, when we assessed the phenotypic changes brought forth by (2) a short-term 1-month-long hNGFp-treatment, starting at 3 months of age (right after the initial presentation of symptoms), we observed the rescue of a well-known neuronal target population of NGF, cholinergic neurons in the medial septum. Moreover, we reveal a deficit in microglial morphology in MeCP2+/- mice, completely reversed in treated animals. This effect on microglia is in line with reports showing microglia to be a TrkA-dependent non-neuronal target cell population of NGF in the brain. To understand the immunomodulatory activity of hNGFp, we analyzed the cytokine profile after hNGFp treatment in MeCP2+/- mice, to discover that the treatment recovered the altered expression of key neuroimmune-communication molecules, such as fractalkine. The overall conclusion is that hNGFp delivered intranasally can ameliorate symptoms in the MeCP2+/- model of Rett syndrome, by exerting strong neuroprotection with a dual mechanism of action: directly on target neurons and indirectly via microglia.

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Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities

Cited by 6 publications

References 78 publications

Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome

Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome

Excitation and Inhibition Imbalance in Rett Syndrome

Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome

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