LOSS OF CDKL5 ALTERS ENTERIC NERVOUS SYSTEM ORGANIZATION AND INTESTINAL FUNCTION IN A MOUSE MODEL OF CDKL5 DEFICIENCY DISORDER

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental condition characterized by early-onset epilepsy, cognitive impairment, and autism-like features. In addition to central nervous system (CNS) dysfunction, CDD patients frequently present gastrointestinal comorbidities, including altered intestinal motility, the underlying mechanisms of which remain largely unexplored. The Cdkl5 knockout (KO) mouse is a well-established model for dissecting CDKL5-dependent CNS alterations. Using this model, we investigated whether CDKL5 deficiency also disrupts the enteric nervous system (ENS) and gastrointestinal function. Analysis of gastrointestinal motility revealed that hemizygous male Cdkl5 KO mice and heterozygous female mice display significant intestinal hypermotility. To explore a possible link between CDKL5 loss and enteric dysfunction, we analyzed Cdkl5 mRNA levels and localization. RNA analyses and in situ hybridization on whole-mount intestinal preparations and enteric plexus–enriched extracts demonstrated that CDKL5 is expressed by enteric neurons. Accordingly, levels of EB2, a known phosphorylation target of CDKL5, were reduced in the intestine of Cdkl5 KO mice. Morphological analysis of the myenteric plexus revealed comparable ganglion size between genotypes, with a trend toward a reduced ganglionic density in Cdkl5 KO mice. While the total number of cells per ganglion was unchanged, ganglion composition was altered, with a reduced proportion of neuronal cells (HuC+) and a relative increase in enteric glial cells (S100+). Overall, these findings identify CDKL5 as a novel component of the enteric nervous system and suggest that its loss leads to functional and cellular alterations of enteric circuits, providing a mechanistic link between CDKL5 deficiency and gastrointestinal dysfunctions.