Current Projects

The creatine-phosphocreatine shuttle rapidly replenishes adenosine triphosphate (ATP) during times of high-energy demand. ATP generated from mitochondrial respiration is converted into phosphocreatine and shuttled to the cytosol to provide a phosphate buffer. The loss of creatine likely leads to increased mitochondrial function that is both inefficient in rapidly replenishing ATP and could be detrimental to long-term cell survival.

Our lab seeks to better understand the changes in mitochondrial function as well as how these changes relate to the cognitive deficits seen in both creatine transporter deficiency (CTD) patients and creatine transporter (CrT) deficient mice. We have developed a mouse model of CTD to better understand the role of creatine in neuronal function. These mice show severe cognitive deficits, suggesting it is a high fidelity model of CTD. Using a combination of cutting edge and well-established methods, we are studying mitochondrial structure and function in CrT knockout mice.
A central question in the field of developmental disorders is, “When do the changes underlying the disorder become permanent?” A better understanding of critical periods is essential in designing treatment strategies. This project seeks to better understand the role of creatine in brain development. We are disrupting creatine transporter (CrT) function at various stages of brain development, followed by examination of behavioral, neuroanatomical and metabolic endpoints. This research will provide valuable information as to the role of creatine in brain development as well as guiding treatment strategies for potential therapeutics.
The role of the creatine transporter (CrT) in the brain is still not fully understood. From patient and animal data, it is clear that the CrT is required for creatine to get into the brain. Presumably, the CrT brings creatine into the brain across the blood brain barrier, and loss of the CrT prevents creatine entry into the brain. However, there are still unanswered questions that require further study to support this hypothesis. For example, in patients with creatine synthesis disorders, why does it take very high doses of creatine for an extended period of time to achieve significant brain creatine levels? In addition, it has been shown that creatine synthesis enzymes are expressed in the brain, suggesting that the brain may be able to make creatine.

In order to better understand how neurons acquire creatine, we are utilizing mice that lack CrT only at the blood-brain barrier. These data studies will significantly affect the design of treatments for CTD and other creatine deficiencies.
Dopamine (DA) is a neurotransmitter that plays an essential role in the brain. DA is involved in cognitive function, motivated behaviors, mood and addiction. The loss of DA neurons is responsible for Parkinson’s Disease. In addition, DA has been implicated in a number of mental disorders such as schizophrenia, bipolar disorder and depression.

Several lines of evidence suggest that creatine is essential for the proper function of DA neurons. For example, creatine supplementation has been shown to delay progression of Parkinson’s Disease. More interestingly, CTD patients are often diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and CrT deficient mice are hyperactive. ADHD is likely mediated through DA, as many of the current treatments of ADHD are drugs that modulate DA release. Our lab seeks to better understand the role of creatine in DA function using genetic, pharmacological and behavioral techniques.
Creatine buffers adenosine triphosphate (ATP) levels, providing rapid energy replenishment during times of high activity. Understanding which cellular systems are the primary consumers of creatine and creatine phosphate will provide valuable insight on the mechanisms that underlie the phenotype observed in creatine transporter deficiency (CTD) patients.

Using 20% of the calories consumed per day, the human brain consumes roughly the same amount of energy as a 20-watt light bulb (despite being only 2% of total body weight). Of that, the Na+,K+-ATPase (NKA) is hypothesized to utilize 60% of the brain’s resting energy. The NKA is responsible for sodium and potassium transport in and out of the cell, which is essential in maintaining resting membrane potentials in neurons. It has been shown that the NKA is dependent on the creatine-phosphocreatine shuttle to function, however the precise mechanism of this relationship and how it relates to overall brain function are still unknown. Using genetic, pharmacological and electrophysiological techniques, our lab seeks to better understand how creatine affects NKA function.
Recent data suggests that patients with bipolar disorder (BD) have significant changes in cellular metabolism. Interestingly, lithium, which is one of the primary treatments of BD, has been shown to alter cellular metabolism via inhibition of glycogen synthesis. The focus of our lab is to better understand how changes in mitochondrial function relate to the phenotypes associated with BD. Further, we seek to better understand the mechanisms that cause the mitochondrial dysfunction seen in BD. The results of these studies will provide significant advancement in the understanding of this debilitating disorder.

Contact Us

A photo of Matthew Skelton.

Matthew R. Skelton, PhD
Assistant Professor, UC Department of Pediatrics

Phone: 513-636-8632

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