Mozaikowy wzór ekspresji CDKL5 u heterozygotycznych samic myszy wiąże się z zależnym od wieku i rejonu remodeling obwodów hamujących

Abstract CDKL5 Deficiency Disorder (CDD) is a severe X-linked encephalopathy that predominantly affects heterozygous females, in whom random X-chromosome inactivation generates mosaic CDKL5 expression. Although early-onset epilepsy is a hallmark of the disorder, the mechanisms by which mosaic CDKL5 loss destabilizes neural circuits over time remain poorly understood. Here, we demonstrate a dynamic, age- and region-dependent remodeling of inhibitory synaptic transmission in heterozygous Cdkl5 (+/–) female mice. At 3 months, inhibitory function is selectively enhanced in the hippocampus, whereas cortical transmission remains unchanged. By 12 months, this profile diverges: hippocampal inhibitory input is reduced, while cortical inhibition is increased. These changes are accompanied by distinct structural alterations. In the hippocampus, presynaptic terminal density follows a biphasic trajectory, together with a persistent reduction of inhibitory postsynaptic sites. In the cortex, a reduction in GABAergic presynaptic markers is observed in association with impaired synaptic organization despite enhanced inhibitory neurotransmission, indicating a dissociation between synaptic structure and function. These alterations occur in the absence of major changes in interneuron density, supporting a model of synaptic and circuit-level remodeling. At the cellular and molecular levels, this phenotype is associated with early microglial activation, age-dependent reduction in GFAP-positive astroglial cells, and altered hippocampal transcriptional trajectories. The analysis of postmortem human cortical tissue suggests age-related changes in inhibitory presynaptic markers consistent with the mouse model. Together, these findings indicate that mosaic CDKL5 deficiency drives region-specific and temporally divergent remodeling of GABAergic circuits rather than a uniform loss of inhibition, identifying inhibitory circuit remodeling as a potential mechanism underlying disease progression in CDD.