Creatine transporter deficiency impairs stress-adaptation and brain energetics homeostasis.

Creatine transporter (CrT) upholds the brain creatine (Cr) levels, but the impacts of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments of CrT-deficiency, the second most common cause of X-linked intellectual disabilities. Herein we examined the consequences of CrT-deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplement. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained the baseline brain ATP level with a tendency towards the pAMPK/autophagy from mTOR signaling activity. Starvation elevated the signaling imbalance and reduced the brain ATP level in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy/mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/NAA (N-acetylaspartate) ratio, partially averted the signaling imbalance, and reduced the infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions of CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplement may be an effective treatment of congenital CrT-deficiency and acute brain injury.