The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Abstract

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

Keywords: animal models; autism; creatine; creatine transporter deficiency; epilepsy; intellectual disability; metabolic disorders; metabolism.

Figure 1

Heatmap representation of the cluster of whole-body animal models for CTD carrying different deletions/mutations of the SLC6A8 gene. Species (M: mouse; R: rat) expression patterns of a mutated allele (C: constitutive; I: inducible) and model generation strategy (KO: knock-out; KI: knock-in) were also cited. The phenotypic traits for each model are indicated (ORT: object-recognition task; MWM: Morris water maze; YM: Y maze; FC: fear conditioning; RM: radial maze; SP: social preference; SG: self-grooming; ROT: rotarod; OF: open field; EZM: elevated zero maze; TST: tail suspension test; LH: learned helplessness; LA: locomotor activity; AS: acoustic startle; SW: swimming behavior; GS: grip strength; PT: pole test; HW: hang wiring; BW: beam walk). Red squares mean significantly higher or lower performance with respect to WT animals. Blue squares refer to phenotypes with no differences between genotypes. Yellow square indicated mixed evidence. Grey squares are for not investigated tasks.

Figure 2

Heatmap representation of the cluster of conditional models for CTD carrying different deletions of SLC6A8gene restricted to specific brain districts. Species (M: mouse), expression pattern of mutated allele (Exc: excitatory neurons; CNS: postmitotic neurons, glial cells and BBB endothelial cells of central nervous system; DA: dopaminergic neurons) and model generation strategy (the promoter driving Cre-recombinase expression) were also cited. The phenotypic traits for each model are indicated (ORT: object-recognition task; MWM: Morris water maze; YM: Y maze; FC: fear conditioning; RM: radial maze; SP: social preference; SG: self-grooming; ROT: rotarod; OF: open field; EZM: elevated zero maze; TST: tail suspension test; LH: learned helplessness; LA: locomotor activity; AS: acoustic startle; SW: swimming behavior; GS: grip strength; PT: pole test; HW: hang wiring; BW: beam walk). Red squares mean significantly higher or lower performance with respect to WT animals. Blue squares refer to phenotypes with no differences between genotypes. Grey squares are for not investigated tasks.