Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

Fuchs, Claudia; Gennaccaro, Laura; Trazzi, Stefania; Bastianini, Stefano; Bettini, Simone; Martire, Viviana Lo; Ren, Elisa; Medici, Giorgio; Zoccoli, Giovanna; Rimondini, Roberto; Ciani, Elisabetta

doi:10.1155/2018/9726950

Cited by 44 publications

(84 citation statements)

References 62 publications

(124 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, Cdkl5 -/y transgenic mice were used as a model for the cyclin-dependent kinase-like 5 (Cdkl5) deficiency disorder (CDD) caused by loss of function mutation in the X-linked Cdkl5. Both diseases are associated with abnormalities in the neuronal architecture in hippocampal and cortical neurons, including simpler dendritic arbors and reduced dendritic lengths starting already at very early stages during development [16,17,36] [21,22,37,38].…”

Section: Fingolimod-phosphate (Fty720-p) Completely Rescues the Neurimentioning

confidence: 99%

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

Patnaik

Spiombi

Frasca

et al. 2020

IJMS

View full text Add to dashboard Cite

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

show abstract

Section: Fingolimod-phosphate (Fty720-p) Completely Rescues the Neurimentioning

confidence: 99%

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

Patnaik

Spiombi

Frasca

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…CDKL5 mutations have been found in CDD patients and in subjects with neurodevelopmental disorders including ASD, atypical Rett syndrome, and early infantile epileptic encephalopathy. Mice lacking CDKL5 display a broad spectrum of behavioral abnormalities, including impaired learning and memory and autisticlike phenotypes (31)(32)(33).…”

Section: Significancementioning

confidence: 99%

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.

View full text Add to dashboard Cite

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.

show abstract

“…Recent studies indicated the role of Mecp2 in social deficits [Ito-Ishida, Ure, Chen, Swann, & Zoghbi, 2015], communication deficits, abnormalities in social interactions, and stereotyped behaviors [Wohr et al, 2015]. Mice lacking CDKL5 displays a broad spectrum of behavioral abnormalities, including impaired learning and memory and autisticlike phenotypes [Amendola et al, 2014;Fuchs et al, 2018;Okuda et al, 2018]. Mutations in Ash2l and Mef2c genes have been identified in human neurological diseases, including ASDs.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

Cited by 44 publications

References 62 publications

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

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

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

Contact Info

Product

Resources

About