In vivo magnetic resonance spectroscopy in the brain of <i>Cdkl5</i> null mice reveals a metabolic profile indicative of mitochondrial dysfunctions

Mutations in the X-linked CDKL5 gene cause deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying clinical symptoms remain largely unknown identification of reliable biomarkers animal models will certainly contribute to increase our comprehension CDD as well assess efficacy therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods disclose structural, functional, or metabolic signatures Cdkl5 brain adult mice. We found that loss does not cerebral atrophy but affects distinct areas, particularly hippocampus. By vivo proton-MR spectroscopy (MRS), revealed null dysregulation indicative mitochondrial dysfunctions. Accordingly, unveiled significant reduction ATP levels decrease expression complex IV electron transport chain. Conversely, number mitochondria appeared preserved. Importantly, reported defect activation one major regulators cellular energy balance, adenosine monophosphate-activated protein kinase (AMPK), might observed impairment become an interesting target for future preclinical trials. In conclusion, MRS presence suggestive dysfunction permitted foster brought interest towards targeting strategy CDD.