DECODING THE OXYTOCIN PATHWAY IN CDKL5-DEFICIENCY DISORDER ​MOUSE MODEL

Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine/threonine kinase highly expressed in the brain and essential for neuronal maturation, synaptic development, and circuit organization within regions critical for motor and cognitive/social behaviour. Pathogenic variants in CDKL5 cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental encephalopathy characterized by early-onset epilepsy, motor impairment, cognitive deficits, and autistic features resulting from widespread synaptic and network dysfunction.
CDKL5 is highly expressed in limbic and hypothalamic circuits that overlap with oxytocin (OT) production and signalling pathways. Because OT modulates social behaviour, emotional processing, and synaptic plasticity in these regions, alterations in OT signalling could contribute to social and cognitive impairments in CDD. Although OT dysregulation is known to be implicated in autism spectrum disorders, its involvement in CDD remains unknown. We therefore hypothesized that social and cognitive deficits in CDD are associated with alterations in the OT system.
We performed immunohistochemical analyses of OT-expressing neurons in three hypothalamic nuclei of adult CDKL5 knockout male mice and heterozygous female mice compared with wild-type littermates.
No significant group differences were observed; however, a trend toward an increased number of oxytocin-positive (OT⁺) neurons was detected in the paraventricular nucleus of heterozygous females, suggesting a potential sex- and region-specific modulation of the oxytocin system in CDKL5 deficiency. This increase may reflect a compensatory response to CDKL5-related synaptic dysfunction rather than a primary pathogenic mechanism. Ongoing studies are investigating OT neuronal subpopulations, receptor expression, and developmental dynamics to clarify the role of CDKL5 in oxytocin-regulated circuits.