Mosaic CDKL5 deficiency drives progressive inhibitory circuit remodelling.

Mosaic CDKL5 deficiency in heterozygous female Cdkl5 mice drives age- and region-specific progressive inhibitory circuit remodeling, including declining hippocampal inhibition and loss of inhibitory presynaptic terminals by 12 months.

• Why it matters: Mosaicism is a defining feature of CDKL5 deficiency disorder, but it is unclear whether it actively shapes disease progression or merely reflects X-inactivation inheritance.
• What they did: Using age-comparative electrophysiology, quantitative synaptic imaging, transcriptomics, and postmortem human brain analyses, the study compared heterozygous and complete Cdkl5 deficiency across hippocampus and cortex at 3 months, middle age, and 12 months.
• The result: Hippocampal inhibition initially increased then declined with age, while cortical inhibitory transmission increased in middle-aged animals; this progressive presynaptic loss was not reproduced by complete Cdkl5 deficiency, and microglial activation (IBA1/CD68 double-positive) rose by 12 months.

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