Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency

Abstract

Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2–4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT−/y (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT−/y mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT−/y mice showed increased average distance from the platform site. CrT−/y mice showed reduced novel object recognition and conditioned fear memory compared to CrT+/y. CrT−/y mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

Regulation of the Na⁺,Cl^- Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

“…Moreover, as creatine biosynthesis consumes 40% of methyl groups and CreaT is regulated by AMPK, creatine is considered a cellular sensor of methylation and energy status [66]. Creatine deficiency disorders including genetic defects of CreaT (SLC6A8) lead to mental retardation, intellectual disability, behavioral disorders, and seizures [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,66]. Those effects could be explained in part by an imbalance of GABAergic and glutamatergic neurotransmission.…”

“…The carrier is expressed in diverse tissues including brain, retina, skeletal muscle, heart, and several epithelia [6,7,8,9]. Loss of function mutations of SLC6A8 result in mental retardation with seizures [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. …”

Upregulation of the Creatine Transporter Slc6A8 by Klotho

“…Slc6A8 is critically important for proper function of the brain, as genetic defects of Slc6A8 lead to mental retardation with seizures [63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]. Slc6A8 deficient mice suffer from learning and memory deficits resembling human Slc6A8 deficiency [63].…”

“…Slc6A8 deficient mice suffer from learning and memory deficits resembling human Slc6A8 deficiency [63]. Consequences of Klotho deficiency include degeneration of mesencephalic dopaminergic neurons [81], an effect, however, reversed by vitamin D restriction [81] and thus presumably not due to direct influence of Klotho on Slc6A8.…”

Upregulation of Na+,Cl--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

“…Those carriers may similarly be candidates for regulation by TTBK2. Genetic defects affecting the creatine transporter CreaT result in mental retardation with seizures [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82]. Defective cellular taurine uptake by TauT fosters apoptosis [83,84,85,86,87,88,89,90,91].…”