Abstract
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.
Highlights
The Cyclin-dependent kinase-like 5 (CDKL5) gene (OMIM #300203) on the chromosome Xp22 region encodes for a serine/threonine kinase, CDKL5 [1]
In the general health check and neurological screening, Cdkl5 -/Y mice showed no significant change in the whisker, coat, righting reflex, whisker-twitch, ear-twitch, reaching, body weight (Fig 1A), but showed a significantly lower rectal temperature compared to the control mice (F1,42 = 16.554, p = 0.0006, one-way ANOVA, Fig 1B)
It is of note that in Cdkl5 +/Y mice, the prepulse inhibition (PPI) induced by 78dB prepulse was larger than that of 74dB prepulse in both startle conditions; in Cdkl5 -/Y mice, 78dB prepulse did not induce larger PPI over 74dB prepulse in either startle condition, and the genotype difference of PPI induced by 78dB prepulse in 120dB startle condition was markedly large (F1,42 = 3.697, p = 0.0613, one-way ANOVA, Fig 1G)
Summary
The Cyclin-dependent kinase-like 5 (CDKL5) gene (OMIM #300203) on the chromosome Xp22 region encodes for a serine/threonine kinase, CDKL5 [1]. CDKL5 is expressed widely in most tissues, with highest levels in brain, thymus, and testis [6]. Within neurons, it localizes in nucleus, neurites, growth cones, dendritic spines, and at the postsynaptic density (PSD) of excitatory synapses [6,7,8,9]. Recent studies have revealed some of its molecular functions, such as the influence on RNA splicing activity by association with the nuclear speckle molecular machinery [10]; brain-derived neurotrophic factor (BDNF)-induced activation of Rho-GTPase Rac, and regulation of neurite outgrowth [8]; the interaction with palmitoylated PSD-95, which regulates synaptic targeting of CDKL5 [11]; the interaction with Shootin 1 to regulate neuronal polarization [12]; and localization at the centrosome and midbody, which is required for faithful cell division [13]. CDKL5 has been to shown to phosphorylate DNA methyltransferase 1 (DNMT1) [14]; amphiphysin 1 [15]; Netrin-G1 ligand (NGL-1) [7]; histone deacetylase 4 (HDAC4) [16]; and Methyl-CpG binding protein 2 (MeCP2), which in turn acts as a transcriptional repressor of Cdkl5 [17, 18]
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