Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Terzic, Barbara; Davatolhagh, M. Felicia; Ho, Yugong; Tang, Sheng; Liu, Yu-Ting; Xia, Zijie; Cui, Yue; Fuccillo, Marc V.; Zhou, Zhaolan

doi:10.1172/jci143655

Cited by 37 publications

(40 citation statements)

References 53 publications

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“…These findings have important implications for future gene therapy studies, since insertion of the isolated kinase domain will facilitate packaging inside viral delivery vectors that have limited space. The potential of this strategy to have therapeutic benefits in individuals with CDD is supported by studies where re-expression of the CDKL5 gene in KO mice fully reversed a cohort of cell, circuit and behavioural phenotypes (Terzic et al, 2021). The finding that CDD appears to be a disorder of neuromaintenance and not neurodevelopment (Kind and Bird, 2021), provides support that expression of the CDKL5 kinase domain later in life may restore specific aspects of brain function.…”

Section: Discussionmentioning

confidence: 99%

“…A number of postsynaptic defects has been observed in a series of CDKL5 KO model systems, such as increased (Okuda et al, 2017; Yennawar et al, 2019) or decreased (Della Sala et al,2016) long-term potentiation, altered dendritic morphology / dynamics (Amendola et al,2014;Della Sala et al, 2016; Tang et al, 2017; Terzic et al, 2021), upregulated NMDA receptor number (Okuda et al, 2017; Tang et al, 2019; Terzic et al, 2021) and a shift in AMPA receptor subunit composition (Yennawar et al, 2019). Furthermore, a number of studies have suggested that loss of CDKL5 impacts synapse numbers in specific brain regions.…”

Section: Discussionmentioning

confidence: 99%

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Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals

Kontaxi

Davenport

Kind

et al. 2022

Preprint

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Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from de novo mutations in the X-linked CDKL5 gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from a Cdkl5 knockout rat model. Using a genetically-encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis. We showed that CDKL5 kinase activity is both necessary and sufficient for optimal SV endocytosis, since kinase-inactive mutations failed to correct endocytosis in CDKL5 knockout neurons, whereas the isolated CDKL5 kinase domain fully restored SV endocytosis kinetics. Finally, we demonstrated that CDKL5-mediated phosphorylation of amphiphysin 1, a putative presynaptic target, is not required for CDKL5-dependent control of SV endocytosis. Overall, our findings reveal a key presynaptic role for CDKL5 kinase activity and enhance our insight into how its dysfunction may culminate in CDD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals

Kontaxi

Davenport

Kind

et al. 2022

Preprint

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“…Several Cdkl5 knockout animal models exist [ 49 , 58 , 65 ] that recapitulate the human disease including learning and memory impairments, autistic-like behaviors and motor deficits, and feature dysmorphic neuronal architecture, disrupted signaling pathways and impaired neuronal connectivity [ 20 , 49 , 54 , 58 , 60–62 , 66–75 ]. Despite extensive investigations, many Cdkl5 animal models lack the development of spontaneous seizures characteristic of CDD [ 49 , 58 ] but some strains are susceptible to N -methyl- d -aspartate (NMDA)-induced seizures [ 61 , 65 , 76 ]. Spontaneous epileptic spasms were described in aged female Cdkl5 mice [ 68 ], and overt, myoclonic and tonic-clonic behavioral seizure-like events were observed in aged animals (>28 weeks) [ 19 ].…”

Section: Cdkl5 Function In Neuronsmentioning

confidence: 99%

“…The lack of these seizure-like events in homozygous females, and hemizygous males implies X-linked mosaicism may drive this phenotype in mice [ 19 ]. Using temporal manipulation of endogenous Cdkl5 in male mice, it was demonstrated that postdevelopmental loss of CDKL5 in mice causes a similar clinical phenotype [ 76 ] to knockout Cdkl5 animal models [ 20 , 49 , 58 , 61 , 66 ]. Excitingly, restoration of Cdkl5 ameliorated the behavioral phenotype and aberrant NMDA receptor signaling [ 76 ], demonstrating for the first time the potential for disease reversal in CDD.…”

Section: Cdkl5 Function In Neuronsmentioning

confidence: 99%

“…Using temporal manipulation of endogenous Cdkl5 in male mice, it was demonstrated that postdevelopmental loss of CDKL5 in mice causes a similar clinical phenotype [ 76 ] to knockout Cdkl5 animal models [ 20 , 49 , 58 , 61 , 66 ]. Excitingly, restoration of Cdkl5 ameliorated the behavioral phenotype and aberrant NMDA receptor signaling [ 76 ], demonstrating for the first time the potential for disease reversal in CDD. The inconsistency of a seizure phenotype may be due to differences between the mouse and human brain neural network [ 77 ].…”

Section: Cdkl5 Function In Neuronsmentioning

confidence: 99%

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CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

Bergen

Massey

Quigley

et al. 2022

Biochemical Society Transactions

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CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.

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Autistic‐relevant behavioral phenotypes of a mouse model of cyclin‐dependent kinase‐like 5 deficiency disorder

Mottolese,

Coiffard,

Ferraguto

et al. 2024

Autism Research

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Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a neurodevelopmental disease caused by mutations in the X‐linked CDKL5 gene and characterized by early‐onset epilepsy, intellectual disability, and autistic features. To date, the etiological mechanisms underlying CDD are largely unknown and no effective therapies are available. The Cdkl5 knock‐out (KO) mouse has been broadly employed in preclinical studies on CDD; Cdkl5‐KO mice display neurobehavioral abnormalities recapitulating most CDD symptoms, including alterations in motor, sensory, cognitive, and social abilities. However, most available preclinical studies have been carried out on adult Cdkl5‐KO mice, so little is known about the phenotypic characteristics of this model earlier during development. Furthermore, major autistic‐relevant phenotypes, for example, social and communication deficits, have been poorly investigated and mostly in male mutants. Here, we assessed the autistic‐relevant behavioral phenotypes of Cdkl5‐KO mice during the first three post‐natal weeks and in adulthood. Males and females were tested, the latter including both heterozygous and homozygous mutants. Cdkl5 mutant pups showed qualitative and quantitative alterations in ultrasonic communication, detected first at 2 weeks of age and confirmed later in adulthood. Increased levels of anxiety‐like behaviors were observed in mutants at 3 weeks and in adulthood, when stereotypies, reduced social interaction and memory deficits were also observed. These behavioral effects of the mutation were evident in both sexes, being more marked and varied in homozygous than heterozygous females. These findings provide novel evidence for the autistic‐relevant behavioral profile of the Cdkl5 mouse model, thus supporting its use in future preclinical studies investigating CDD pathology and autism spectrum disorders.

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Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Cited by 37 publications

References 53 publications

Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals

Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

Autistic‐relevant behavioral phenotypes of a mouse model of cyclin‐dependent kinase‐like 5 deficiency disorder

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