Abstract
Mutations in creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CTD), an orphan neurodevelopmental disorder presenting with brain Cr deficiency, intellectual disability, seizures, movement and autistic-like behavioral disturbances, language and speech impairment. We have recently generated a murine model of CTD obtained by ubiquitous deletion of 5–7 exons in the CrT gene. These mice showed a marked Cr depletion, associated to early and progressive cognitive impairment, and autistic-like defects, thus resembling the key features of human CTD. Given the importance of extraneural dysfunctions in neurodevelopmental disorders, here we analyzed the specific role of neural Cr in the CTD phenotype. We induced the conditional deletion of Slc6a8 gene in neuronal and glial cells by crossing CrT floxed mice with the Nestin::Cre recombinase Tg (Nes-cre) 1Kln mouse. We report that nervous system-specific Cr depletion leads to a progressive cognitive regression starting in the adult age. No autistic-like features, including repetitive and stereotyped movements, routines and rituals, are present in this model. These results indicate that Cr depletion in the nervous system is a pivotal cause of the CTD pathological phenotype, in particular with regard to the cognitive domain, but extraneural actors also play a role.
Highlights
Preclinical animal models are crucial tools to dissect disease pathogenic mechanisms and develop new therapeutic strategies
We found a specific decrease of Cr in the cerebral cortex and the hippocampus of mutant animals with respect to wild-type mice (CrT+/y) and Cre-recombinase expressing littermates, while no significant difference was observed between CrT+/y and nes-CrT+/y animals[14] (Fig. 1)
This is the first longitudinal analysis of behavioral deficit in a conditional CrT mouse model, showing a late onset of cognitive symptoms associated with progressive learning and memory deterioration which further culminates in one-year old animals as a broad spectrum impairment of declarative, spatial and working memory
Summary
Preclinical animal models are crucial tools to dissect disease pathogenic mechanisms and develop new therapeutic strategies. The broad spectrum of phenotypes displayed by CrT−/y mice reproduced the key clinical features of CTD patients and strongly established the face validity and the utility of this model for translational studies. Knockout mouse[14,18] (nes-CrT−/y) with the aim to dissect the role of neural Cr in CTD. To what reported by Udobi et al.[15], adult nes-CrT−/y mice carrying the deletion of exons 5–7 present a remarkable Cr depletion restricted to the nervous system leading to a significant cognitive deficit[14,15]. We performed a longitudinal evalutation of cognitive functions in nes-CrT−/y mice, and we explored various autistic-like and motor behaviors in order to provide a normative portrait of conditional CTD mouse model relevant in translational perspective
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