Reigning in Excitatory Signaling in CDKL5 Deficiency.

Abstract

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder Yennawar M, White RS, Jensen FE. J Neurosci. 2019;39(24):4814-4828. doi:10.1523/JNEUROSCI.2041-18.2019Pathogenic 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 (PTZ) administration. Furthermore, we observed a specific increase in GluA2-lacking AMPA receptors (AMPARs) in the adultR59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR excitatory postsynaptic currents 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. Altered NMDAR Signaling Underlies Autistic-Like Features in Mouse Models of CDKL5 Deficiency Disorder Tang S, Terzic B, Wang IJ, et al. Nat Commun. 2019;10(1):2655.Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic N-methyl-D-aspartate (NMDA) receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.