Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits
Barbara Terzic, … , Marc V. Fuccillo, Zhaolan Zhou
Barbara Terzic, … , Marc V. Fuccillo, Zhaolan Zhou
Published October 15, 2021
Citation Information: J Clin Invest. 2021;131(20):e143655. https://doi.org/10.1172/JCI143655.
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Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Abstract

CDKL5 deficiency disorder (CDD) is an early onset, neurodevelopmental syndrome associated with pathogenic variants in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). CDKL5 has been implicated in neuronal synapse maturation, yet its postdevelopmental necessity and the reversibility of CDD-associated impairments remain unknown. We temporally manipulated endogenous Cdkl5 expression in male mice and found that postdevelopmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain. Accordingly, restoration of Cdkl5 after the early stages of brain development using a conditional rescue mouse model ameliorated CDD-related behavioral impairments and aberrant NMDA receptor signaling. These findings highlight the requirement of CDKL5 beyond early development, underscore the potential for disease reversal in CDD, and suggest that a broad therapeutic time window exists for potential treatment of CDD-related deficits.

Authors

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

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Figure 4

Adult restoration of CDKL5 abrogates aberrant NMDAR-mediated synaptic responses.

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Adult restoration of CDKL5 abrogates aberrant NMDAR-mediated synaptic re...
(A) Representative Western blots showing several major ionotropic glutamate receptor subunits from PSD membrane fractions in CreER, STOP, and Res mice. (B–E) STOP, but not Res, mice show a selective increase in levels of GluN2B, a major subunit of the NMDAR, compared with CreER littermate controls (n = 8 per genotype). (F) STOP, but not Res, mice show a significantly increased susceptibility to NMDA-induced seizures compared with CreER littermate controls (CreER, n = 9; STOP, n = 10; Res, n = 9). (G–I) STOP, but not Res, mice show an increased ratio of NMDA-mediated to AMPA-mediated synaptic responses (NA) in the hippocampal CA1 (G) concomitant with a significantly larger decay time constant of NMDAR-mediated EPSCs (I) when compared with CreER littermates. Representative traces are shown in H. This suggests a higher contribution of GluN2B-containing NMDARs in STOP mice and an attenuation of aberrant NMDAR signaling deficits in Res mice. For all panels, Kruskal-Wallis test with Dunn’s multiple-comparison test, except for G and I, which used 1-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05; **P < 0.01; ***P < 0.001. Data are represented as mean ± SEM. Full-scan Western blots of all samples are available in the supplemental material.