Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder

Abstract

CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD.

Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice

“…However, the protein level of PSD-95, a CDKL5-interacting protein in the postsynaptic density, appeared to be reduced in pups lacking CDKL5 (0.812 ± 0.049 of WT, p < 0.01; Fig. 7A, D), consistent with previous studies in mutant mice and in cultured neurons (Ricciardi et al, 2012;Zhu et al, 2013;Della Sala et al, 2016;Pizzo et al, 2016;Lupori et al, 2019). Thus, KCC2 phosphorylation at S940 appears to be selectively down-regulated in Cdkl5 null pups, especially at the age when they are suffering from spontaneous seizures.…”

Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency

“…Animals were fixed under the objective using a magnet mounted on an arduino-based imaging chamber. Red light illumination (630 nm) was obtained with 8 individually addressable LEDs (WS2812) secured to the objective (Leica PanApo 2.0X 10447170) by a custom 3D printed holder 41 . Visual stimuli were generated using Matlab Psychtoolbox and displayed on a screen placed 13 cm away from the eyes of the animals.…”

Novel translational phenotypes and biomarkers for creatine transporter deficiency

“…EEG and sensory-evoked responses are readily applicable to humans and widely used for non-invasive assessment of cortical function, making electrophysiological measurements or functional imaging ecologically ideal translational tools for functional analyses in children with neurodevelopmental disorders ( Nelson and McCleery, 2008 ; Lloyd-Fox et al , 2010 ; Vanderwert and Nelson, 2014 ). Accordingly, previous studies reported that a standardized inspection of EEG and cortical responses to sensory stimuli is suitable to reveal, in both animal models and patients, stage-specific alterations in other disorders affecting neurodevelopment ( Bosl et al , 2011 ; Durand et al , 2012 ; LeBlanc et al , 2015 ; Boggio et al , 2016 ; Mazziotti et al , 2017 ; Bowman and Varcin, 2018 ; Lupori et al , 2019 ). Abnormal EEG waveforms have been previously documented in creatine transporter deficiency patients, indicating diffuse slowing, interictal theta activity, specific sharp abnormalities and focal/generalized paroxysmal or slow abnormalities ( Schiaffino et al , 2005 ; Póo-Argüelles et al , 2006 ; Mancardi et al , 2007 ; Fons et al , 2009 ; Leuzzi et al , 2013 ).…”