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other·preclinical research, neurology, biomedical research, pediatric ophthalmology·PMC10527551

Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder

Biomolecules · 10 authors, 2 centres

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TL;DR

This preclinical study tested voluntary wheel running in Cdkl5 knockout mice, a model of CDKL5 deficiency disorder. The central result is that long-term running improved behavioral deficits (hyperlocomotion, impulsivity) and was associated with increased hippocampal neurogenesis, neuronal survival, spine maturation, and BDNF levels.

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The study used a preclinical mouse model of CDKL5 deficiency disorder (CDD) to investigate the effects of voluntary wheel running. The study design involved comparing wild-type and Cdkl5 knockout mice, with a subset of each genotype having access to running wheels. Key results indicated that voluntary running in the knockout mice reduced hyperlocomotion and impulsivity in an open-field test to wild-type levels and showed a trend towards improved memory in a passive avoidance task. Structurally, running increased hippocampal neurogenesis, improved survival of CA1 pyramidal neurons, inhibited microglia overactivation, and promoted cortical dendritic spine maturation. A proposed mechanism involves exercise-induced upregulation of BDNF. Limitations include the use of a mouse model, which may not perfectly recapitulate human CDD, and the observation that the knockout mice ran significantly less than wild-type mice, raising questions about motivation and skill learning. The authors suggest that a properly designed exercise program could be a beneficial adjuvant therapy for CDD patients.

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preclinical research

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ORIGINAL PAPER

PMC10527551

Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder

Biomolecules

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ABSTRACT

Abstract Cyclin-dependent kinase-like 5 ( CDKL5 ) deficiency disorder (CDD) is a rare neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene. CDD is characterized by a broad spectrum of clinical manifestations, including early-onset refractory epileptic seizures, intellectual disability, hypotonia, visual disturbances, and autism-like features. The Cdkl5 knockout (KO) mouse recapitulates several features of CDD, including autistic-like behavior, impaired learning and memory, and motor stereotypies. These behavioral alterations are accompanied by diminished neuronal maturation and survival, reduced dendritic branching and spine maturation, and marked microglia activation. There is currently no cure or effective treatment to ameliorate the symptoms of the disease. Aerobic exercise is known to exert multiple beneficial effects in the brain, not only by increasing neurogenesis, but also by improving motor and cognitive tasks. To date, no studies have analyzed the effect of physical exercise on the phenotype of a CDD mouse model. In view of the positive effects of voluntary running on the brain of mouse models of various human neurodevelopmental disorders, we sought to determine whether voluntary daily running, sustained over a month, could improve brain development and behavioral defects in Cdkl5 KO mice. Our study showed that long-term voluntary running improved the hyperlocomotion and impulsivity behaviors and memory performance of Cdkl5 KO mice. This is correlated with increased hippocampal neurogenesis, neuronal survival, spine maturation, and inhibition of microglia activation. These behavioral and structural improvements were associated with increased BDNF levels. Given the positive effects of BDNF on brain development and function, the present findings support the positive benefits of exercise as an adjuvant therapy for CDD. Keywords: Cdkl5 KO mice, voluntary exercise, brain development, dendritic pathology, neuronal survival, neuroinflammation

CITATION EXPORT

Nicola Mottolese, Beatrice Uguagliati, Marianna Tassinari et al.. Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Biomolecules. (2023). https://doi.org/10.3390/biom13091396

AUTHORS

10 · 2 CENTRES

Nicola Mottolese, Beatrice Uguagliati, Marianna Tassinari, Camilla Bruna Cerchier, Manuela Loi, Giulia Candini, Roberto Rimondini, Giorgio Medici, Stefania Trazzi, Elisabetta Ciani

1Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
2Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy

Nicola Mottolese, Beatrice Uguagliati, Marianna Tassinari et al.. Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Biomolecules. (2023). https://doi.org/10.3390/biom13091396