Mouse model of creatine transporter deficiency reveals brain-region-specific protein changes as development unfolds

Creatine is central to cellular energy buffering, and the brain relies on the creatine transporter (CRT, encoded by SLC6A8) to import it across the plasma membrane, including at the blood–brain barrier and in neurons. Pathogenic SLC6A8 variants cause creatine transporter deficiency (CTD), which depletes brain creatine and leads to cognitive impairment. Because there are few effective treatments, understanding how the deficiency reshapes the developing brain at the molecular level is a priority. This summary is based on the abstract and metadata provided; the full methods and results sections were not available.

The researchers focused on the c.1681G>C (G561R) variant, which corresponds to a variant found in a patient with CTD. First, they expressed the mouse CRT carrying this variant in HEK293 cells. The mutant transporter showed impaired N-glycan maturation and poor localization to the plasma membrane, producing markedly reduced creatine uptake. This is consistent with earlier reports on the equivalent human variant. They then used CRISPR/Cas9 to create knock-in mice carrying the same point mutation in Slc6a8.

Male knock-in mice showed severe reductions in brain creatine, postnatal growth retardation and impaired spatial memory, even though gross brain morphology was preserved. The cognitive and metabolic deficits therefore appear to arise from molecular and functional disruption rather than overt structural damage. The authors then ran quantitative proteomics on the hippocampus and cerebral cortex at several stages of postnatal development. The abstract names SWATH-MS as the method.

The proteomic changes depended on both brain region and developmental stage. The hippocampus showed pronounced early postnatal remodeling, particularly in proteins involved in actin cytoskeleton organization and vesicle-mediated membrane trafficking. These processes underlie synaptic structure and function, which may relate to the spatial memory deficits. The cerebral cortex responded more gradually. Its changes involved creatine biosynthesis-related enzymes, which may reflect a compensatory attempt to offset creatine loss. Later-emerging mitochondrial pathways followed, including the mitochondrial translation machinery.

Taken together, the findings suggest that CTD is not a uniform energetic deficit. Different brain regions seem to adapt, or fail to adapt, on different timelines. If confirmed, this could help define windows for intervention and region-specific biomarkers or targets, and it provides a validated preclinical model for testing therapies. Caveats include the use of a single missense variant, apparently male mice only, and a proteomic approach that shows association rather than causation. Whether these pathway changes drive the cognitive phenotype, and whether they carry over to patients, remains to be shown.