Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 19 July 2023 / Approved: 20 July 2023 / Online: 20 July 2023 (08:38:33 CEST)
Version 2 : Received: 6 September 2023 / Approved: 7 September 2023 / Online: 7 September 2023 (11:25:05 CEST)

A peer-reviewed article of this Preprint also exists.

Mottolese, N.; Uguagliati, B.; Tassinari, M.; Cerchier, C.B.; Loi, M.; Candini, G.; Rimondini, R.; Medici, G.; Trazzi, S.; Ciani, E. Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Biomolecules 2023, 13, 1396. Mottolese, N.; Uguagliati, B.; Tassinari, M.; Cerchier, C.B.; Loi, M.; Candini, G.; Rimondini, R.; Medici, G.; Trazzi, S.; Ciani, E. Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Biomolecules 2023, 13, 1396.

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 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

Subject

Biology and Life Sciences, Neuroscience and Neurology

Comments (1)

Comment 1
Received: 7 September 2023
Commenter: Nicola Mottolese
Commenter's Conflict of Interests: Author
Comment: The new version of the manuscript includes important clarifications in the text for a better understanding of the experiment and results, as well as an improvement in the statistical analysis.
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