ABSTRACT
The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for 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 supplementation. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy and 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/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.
Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Brain/metabolism , Creatine/deficiency , DNA/genetics , Membrane Transport Proteins/genetics , Mental Retardation, X-Linked/genetics , Mutation , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Animals , Animals, Newborn , Brain/ultrastructure , Brain Diseases, Metabolic, Inborn/metabolism , Brain Diseases, Metabolic, Inborn/pathology , Creatine/genetics , Creatine/metabolism , DNA Mutational Analysis , Disease Models, Animal , Homeostasis , Male , Membrane Transport Proteins/deficiency , Mental Retardation, X-Linked/metabolism , Mental Retardation, X-Linked/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Microscopy, Electron , Neurons/metabolism , Neurons/ultrastructure , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/metabolismABSTRACT
ATBF1 is a large nuclear protein that contains multiple zinc-finger motifs and four homeodomains. In mammals, ATBF1 regulates differentiation, and its mutation and/or downregulation is involved in tumorigenesis in several organs. To gain more insight into the physiological functions of ATBF1, we generated and validated a conditional allele of mouse Atbf1 in which exons 7 and 8 were flanked by loxP sites (Atbf1(flox) ). Germline deletion of a single Atbf1 allele was achieved by breeding to EIIa-cre transgenic mice, and Atbf1 heterozygous mice displayed reduced body weight, preweaning mortality, increased cell proliferation, and attenuated cytokeratin 18 expression, indicating haploinsufficiency of Atbf1. Floxed Atbf1 mice will help us understand such biological processes as neuronal differentiation and tumorigenesis.
