Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Simicic

et al. 2021

Sci Rep

Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8Y389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Simicic

et al. 2021

Sci Rep

“…Interestingly, while WT males showed higher levels of Cr in plasma than in CSF, Slc6a8 xY389C/y KI males exhibited similar levels in both liquids (60-70 μmol/l). Altogether, these data support the fact that the Cr pool in CNS does not fully depend on the peripheral one, owing to the low permeability of blood-brain barrier for Cr and to brain endogenous synthesis of Cr 9,37,39,40 .…”

Section: Discusionsupporting

confidence: 60%

“…Ubiquitous CrT KO males with exons 5-8 deleted showed impaired motor function 12 . Cognitive deficits with normal sociability were demonstrated in the ubiquitous KO males with deletions in exons 2-4 9,16 and 5-7 13,14 . Deletion in exons 2-4 also caused some changes in monoamine neurotransmitters correlating with higher resilience to stress, while deletion in exons 5-7 leaded to more stereotypies, impaired working memory performance and some brain alterations associated with aging.…”

Section: Introductionmentioning

confidence: 99%

“…To better understand the pathology and with the ultimate goal of finding a treatment, several mouse models for CTD have been generated 9-16 . In particular, CrT knock-out (KO) mouse males with ubiquitous deletions of the exons 2-4 9,16 , 5-7 13,14 and 5-8 12 showed brain creatine deficiency and decreased body weight, features present in CTD patients 17 . Ubiquitous CrT KO males with exons 5-8 deleted showed impaired motor function 12 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Simicic

et al. 2020

Preprint

Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

Creatine transporter–deficient rat model shows motor dysfunction, cerebellar alterations, and muscle creatine deficiency without muscle atrophy

Grosse

et al. 2021

J of Inher Metab Disea

Creatine (Cr) is a nitrogenous organic acid and plays roles such as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes arginine:glycine amidinotransferase and guanidinoacetate methyltransferase, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause creatine deficiency syndromes (CDS). CDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. Among CDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies, and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models, and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8 Y389C knock-in rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency, and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunctions, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.