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

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.

Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder

“…To establish the effect of treatment with P021 on hippocampal neurogenesis, we rst evaluated the number of BrdU-positive cells in the hippocampal dentate gyrus (DG). As previously reported [31], no difference in the number of BrdU-positive cells was found between Cdkl5 −/Y and Cdkl5 +/Y mice (Fig. 3A); treatment with P021 showed a small but non-signi cant increase on progenitor cell proliferation (Fig.…”

“…Recent ndings have indicated that neurotrophic factors such as BDNF can serve as potential therapeutic candidates in neurodevelopmental disorders such as Rett syndrome and CDD [30,31,56,57]. In this study, we examined the effects of a CNTF-derived peptidergic compound, P021, on neuronal maturation and survival in a human cellular model and in a mouse model of CDD.…”

“…Cdkl5 KO mice are characterized by increased microglial activation [21,22,31]. Since it has been demonstrated that CNTF inhibits microglial activation [54], we explored whether treatment with P021 improves microglial cell status in the cortex of Cdkl5 −/Y mice.…”

“…Among these, neurotrophic factors, such as BDNF and IGF-1, by virtue of their neurogenic and neurotrophic activities, were found to have positive effects on the brain phenotypes of Cdkl5 KO mice [15,22,29,30]. In particular, boosting the BDNF/TrkB pathway with a TrkB agonist [30] or increasing BDNF expression by voluntary exercise [31] improves memory performance of Cdkl5 KO mice.…”

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…Compared to sedentary controls, both Cdk l5 KO mice ( 262 ) and VPA-induced rats ( 204 ) after one month of wheel/treadmill running showed increased hippocampal neurogenesis, improved memory performance, and reduced anxious and impulsive behaviors. One-month voluntary wheel running not only can decrease hippocampal microglia overactivation in Cdkl5 KO mice ( 262 ), but also stimulate microglia-mediated engulfment of surplus synapses in the granule cell axons observed in MIA mice ( 229 ). On the other hand, however, high-intensity exercise may produce negative effects on ASD symptoms.…”