Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis

Herrera, Julián A.; Ward, Christopher; Wehrens, Xander H.T.; Neul, Jeffrey L.

doi:10.1093/hmg/ddw326

Cited by 12 publications

(22 citation statements)

References 42 publications

(63 reference statements)

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“…3C). This is consistent with cholinergic circuits mediating pupillary fluctuations (37-40) and altered cholinergic drive in both BTBR and RTT mouse models (27,(39)(40)(41)(42).…”

Section: Significancesupporting

confidence: 83%

“…3). While altered cholinergic drive in BTBR and MeCP2-deficient mice has been documented (27,(39)(40)(41)(42)(45)(46)(47), ours is an indication of a similar abnormality in CDKL5 mutants, suggesting further studies in preclinical and clinical setting.…”

Section: Significancementioning

confidence: 51%

“…This targeted rescue was sufficient to prevent the arousal fluctuation phenotype (Fig. 3), while these mice continued to develop hindlimb clasping and motor deficits (39,42). In addition, impaired pupillary reflex, further indicative of cholinergic impairment, was observed in LYNX1 KO mice and rescued in the MeCP2 Stop/y ::ChatCre +/− line (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 94%

“…Among the adult cohorts, ConvNetACh gave the highest score to BTBR mice, followed by the MeCP2 stop/y males, and then the CDKL5 KO mice. Notably, ConvNetACh specifically selected for the "altered cholinergic trait" of the disorder spectrum, as demonstrated by a lack of response to the case of MeCP2 Stop/y ::ChatCre +/− mice, in which any cholinergicmediated phenotype was rescued while preserving other RTT phenotypes (39,42).…”

Section: Significancementioning

confidence: 99%

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Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients

Artoni

Piffer

Vinci

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Neurodevelopmental spectrum disorders like autism (ASD) are diagnosed, on average, beyond age 4 y, after multiple critical periods of brain development close and behavioral intervention becomes less effective. This raises the urgent need for quantitative, noninvasive, and translational biomarkers for their early detection and tracking. We found that both idiopathic (BTBR) and genetic (CDKL5- and MeCP2-deficient) mouse models of ASD display an early, impaired cholinergic neuromodulation as reflected in altered spontaneous pupil fluctuations. Abnormalities were already present before the onset of symptoms and were rescued by the selective expression of MeCP2 in cholinergic circuits. Hence, we trained a neural network (ConvNetACh) to recognize, with 97% accuracy, patterns of these arousal fluctuations in mice with enhanced cholinergic sensitivity (LYNX1-deficient). ConvNetACh then successfully detected impairments in all ASD mouse models tested except in MeCP2-rescued mice. By retraining only the last layers of ConvNetACh with heart rate variation data (a similar proxy of arousal) directly from Rett syndrome patients, we generated ConvNetPatients, a neural network capable of distinguishing them from typically developing subjects. Even with small cohorts of rare patients, our approach exhibited significant accuracy before (80% in the first and second year of life) and into regression (88% in stage III patients). Thus, transfer learning across species and modalities establishes spontaneous arousal fluctuations combined with deep learning as a robust noninvasive, quantitative, and sensitive translational biomarker for the rapid and early detection of neurodevelopmental disorders before major symptom onset.

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“…3C). This is consistent with cholinergic circuits mediating pupillary fluctuations (37-40) and altered cholinergic drive in both BTBR and RTT mouse models (27,(39)(40)(41)(42).…”

Section: Significancesupporting

confidence: 83%

Section: Significancementioning

confidence: 51%

Section: Significancementioning

confidence: 94%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients

Artoni

Piffer

Vinci

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…However, at least 5% of typical forms and more other atypical forms are not linked to any of 4 genes known to be involved in the disease. Sudden unexpected death occurs in one-quarter of deaths caused by RTT (10). The course and severity of RTT are determined by the location, type, severity of mutation and X-inactivation.…”

Section: An Incurable Neurological Disorder-rett Syndrome (Rtt)mentioning

confidence: 99%

Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology

Gomathi

Vellingiri

2017

Stem Cell Investig.

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Recent advances in induced pluripotent stem cell (iPSC) technology target screening and discovering of therapeutic agents for the possible cure of human diseases. Human induced pluripotent stem cells (hiPSC) are the right kind of platform for testing potency of specific active compounds. Ayurveda, the Indian traditional system of medicine developed between 2,500 and 500 BC, is a science involving the intelligent formulations of herbs and minerals. It can serve as a "goldmine" for novel neuroprotective agents used for centuries to treat neurological disorders. This review discusses limitations in screening drugs for neurological disorders and the advantages offered by hiPSC integrated with Indian traditional system of medicine. We begin by describing the current state of hiPSC technology in research on Rett syndrome (RTT) followed by the current controversies in RTT research combined with the emergence of patient-specific hiPSC that indicate an urgent need for researchers to understand the etiology and drug mechanism. We conclude by offering recommendations to reinforce the screening of active compounds present in the ayurvedic medicines using the human induced pluripotent neural model system for research involving drug discovery for RTT. This integrative approach will fill the current knowledge gap in the traditional medicines and drug discovery.

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The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

Mahmood

Aldhalaan²,

Alshammari

et al. 2020

Autism Research

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Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three‐chamber social interaction, self‐grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. Lay Summary The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism‐related behavioral features. In addition, the brain of the autistic‐like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311–1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis

Cited by 12 publications

References 42 publications

Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients

Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients

Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology

The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

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