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1.
Eur J Neurosci ; 59(12): 3337-3352, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38654472

ABSTRACT

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.


Subject(s)
Cannabidiol , Protein Serine-Threonine Kinases , Seizures , Animals , Cannabidiol/pharmacology , Seizures/drug therapy , Seizures/genetics , Seizures/metabolism , Mice , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/metabolism , Epileptic Syndromes/genetics , Epileptic Syndromes/drug therapy , Pentylenetetrazole , Hippocampus/metabolism , Hippocampus/drug effects , Disease Models, Animal , Gene Knock-In Techniques/methods , Male , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Endocannabinoids/metabolism , Behavior, Animal/drug effects , Mice, Inbred C57BL , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Spasms, Infantile , Receptors, Cannabinoid
2.
J Neurosci ; 39(24): 4814-4828, 2019 06 12.
Article in English | MEDLINE | ID: mdl-30952813

ABSTRACT

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.SIGNIFICANCE STATEMENT CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.


Subject(s)
Epileptic Syndromes/drug therapy , Epileptic Syndromes/genetics , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/genetics , Receptors, AMPA/drug effects , Spasms, Infantile/drug therapy , Spasms, Infantile/genetics , Adult , Animals , Behavior, Animal , Child, Preschool , Disease Models, Animal , Epileptic Syndromes/psychology , Excitatory Postsynaptic Potentials/genetics , Female , Gene Knock-In Techniques , Humans , Learning Disabilities/genetics , Learning Disabilities/psychology , Male , Memory Disorders/genetics , Memory Disorders/psychology , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mutation/genetics , Psychomotor Performance , Receptors, AMPA/deficiency , Receptors, AMPA/genetics , Seizures/chemically induced , Seizures/physiopathology , Social Behavior , Spasms, Infantile/psychology
3.
PLoS Biol ; 16(6): e2006459, 2018 06.
Article in English | MEDLINE | ID: mdl-29953453

ABSTRACT

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.


Subject(s)
Mutation Rate , RNA Viruses/genetics , RNA Viruses/pathogenicity , Virulence/genetics , 3T3 Cells , Amino Acid Substitution , Animals , Directed Molecular Evolution , Female , Host Microbial Interactions/genetics , Kinetics , Male , Mice , Mice, Transgenic , Models, Genetic , Mutagenesis, Site-Directed , Polymorphism, Single Nucleotide , RNA Viruses/physiology , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Theilovirus/genetics , Theilovirus/pathogenicity , Theilovirus/physiology , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Replication/genetics
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