Abstract
Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5−/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5−/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5−/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.
Highlights
De novo mutations of the cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the Hanefeld variant of Rett syndrome (RTT), referred to as Cyclin-dependent kinase-like 5 (CDKL5) disorder
We evaluated whether structural excitation and inhibition (E/I) abnormalities could result from the lack of CDKL5 by investigating the organization of excitatory and inhibitory synapses in the cerebral cortex of Cdkl5 KO mice
Because the correct organization of the PV system is crucial for the critical period (CP) of ocular dominance plasticity (ODP) in the visual cortex (Levelt and Hübener, 2012), we investigated whether Cdkl5 deletion may tamper with the developmental trajectory of cortical circuitry refinement
Summary
De novo mutations of the cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the Hanefeld variant of Rett syndrome (RTT), referred to as CDKL5 disorder. CDKL5 encodes a ubiquitously expressed serine/threonine kinase whose catalytic domain shares homology with members of the cyclin-dependent kinase family and mitogen-activated protein kinases (Montini et al, 1998). This kinase is expressed at high levels in the brain, reaching a peak during postnatal development, when crucial events occur, such as neuronal maturation and synaptogenesis (Rusconi et al, 2008; KilstrupNielsen et al, 2012). By phosphorylating netrin-G1 ligand (NGL-1), CDKL5 can modulate the association of this cell adhesion molecule with PSD-95, thereby contributing to regulate the structural organization of dendritic spines and excitatory synapse function (Ricciardi et al, 2012)
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