Behavioural and morphological analysis of the arousal system in CDKL5 deficiency disorder animal model

CDKL5 deficiency disorder is a severe and rare X-linked neurodevelopmental disease. This disorder results in a pathological mutation of the CDKL5 protein, leading to a range of complications. The development of the murine animal model for CDD has been a valuable tool to investigate the mechanisms underlying this disorder. Various studies have demonstrated that mice lacking CDKL5 develop behavioural phenotypes that mimic features of autism and core symptoms of attention-deficit hyperactivity disorder (ADHD), like locomotor activity and impulsivity. These phenotypes have been linked to dysregulation of arousal. The first phase of our research aimed to investigate morphological structures of the CNS that play important roles in the arousal system. Immunohistochemistry staining was performed starting from the retina to analyse melanopsin retinal ganglion cells, involved in the non-visual functions of the eye, and the retinal pigment epithelium, a layer of cells that is vital for retinal homeostasis. We then moved to more central areas to investigate the orexin system, which regulates sleep–wake cycle and arousal. We evaluated orexin neuron population in the lateral hypothalamus and their projections to the locus coeruleus. In the second phase we analysed the therapeutic effect of Suvorexant, a double orexin receptor antagonist, on the hyperactivity of CDKL5 KO mice. This was done through pupillometry by detecting changes in arousal through the measurement of pupil size fluctuations over time and locomotor activity in basal conditions.