Monday, June 26, 2017

Loss of metabolic enzyme in mouse brains impairs long-term spatial memory


ACSS2 enzyme, which is required for long-term spatial memory, relocates to the cell nucleus where gene expression occurs. Image shows mouse neurons from the hippocampus. Neuron nuclei are stained blue and ACSS2 enzyme is red, so overlap is pink-purple. The axons are green. Image credit: University of Pennsylvania

When certain “memory genes” are expressed, we develop memories—our first day of school, summer vacations, the first date with our partner. A new study in mice shows that, for at least one type of memory, this critical gene expression process is driven by the activity of a metabolic enzyme located right at the DNA in the nucleus of specific neurons. Reducing the activity of this enzyme, known as acetyl-CoA synthetase 2 (ACSS2), in hippocampal neurons of adult mice impairs long-term spatial memory.

“We typically think of metabolism as the body using enzymatic pathways to convert food into energy,” says Ted Abel, PhD, director of the Iowa Neuroscience Institute at the University of Iowa Carver College of Medicine, and an author on the study that was published recently in the journal Nature. “What this shows is that metabolism doesn’t just happen at a cellular level, it happens at a subcellular level, even at the DNA in the nucleus, and that this ‘local’ metabolism can drive behavior.”


Ted Abel, PhD

Abel, an expert in cellular and molecular mechanisms of long-term memory storage, recently moved to the UI to lead the Iowa Neuroscience Institute. The study was done with colleagues at the Perelman School of Medicine at the University of Pennsylvania, where Abel was previously a faculty member.

For genes to be expressed, DNA, which is tightly coiled around proteins known as histones in the cell nucleus, has to unwind a little. Adding a small chemical tag called an acetyl group to the histone protein loosens the structure enough to allow gene expression. This histone acetylation requires a local supply of a metabolite called acetyl–CoA, which is made by two enzymes, ACSS2 and ATP-citrate lyase (ACL). Although it was well known that histone acetylation is critical for the formation of spatial memory, the source of the acetyl-CoA and the mechanism for acetylating histones was not clear.

Previous animal studies have shown that boosting histone acetylation in neurons can both reverse cognitive deficits in mouse models of neurodegeneration and enhance cognition in healthy animals.

In the new study, reducing histone acetylation (by reducing the activity of the ASSC2 enzyme) led to deficits in long-term spatial memory in mice—the animals were not able to remember where objects had been placed in an experimental environment. The findings suggest that manipulating histone acetylation might provide a new way to treat diseases that cause memory and cognitive problems, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and even depression.

Location, location, location

In the new work, the researchers followed up on their observation that ACSS2 is present at high levels in neurons of the hippocampus, a brain region that is involved in spatial memory.

Observing neurons as they matured in a petri dish, the researchers made the surprising discovery that the ACSS2 enzyme relocates to the cell nucleus where gene expression occurs. In contrast, the other acetyl-CoA-producing enzyme, ACL, remains outside the nucleus in the cell’s cytoplasm. The study also showed that this movement of ACSS2 into the nucleus is correlated with increased histone acetylation in areas of the DNA required for expression of important neuron-specific memory genes.

“Probably the most striking finding (of the new study) was that the source of the metabolite acetyl-CoA (the ASSC2 enzyme) is found right on chromatin (the complex of DNA wound around histone proteins) at the particular genes that are going to be actively expressed when you learn something,” Abel says. “So, it is literally like having the source, the engine, right there to drive the acetylation-promoted gene expression.”

Potential new target for therapy

Interestingly, histone acetylation has also been identified as a drug target for treating cancer, and there are drugs that modify histone acetylation that are currently being tested in cancer clinical trials. However, those drugs are not yet being tested in neurological or psychiatric disorders that affect memory or cognition.

The study also found that histone acetylation was important during neuronal development and differentiation. Abel notes that although the ramifications of this finding are not fully understood, it might suggest a connection between abnormal histone acetylation and developmental problems such as autism or intellectual disability.

“We are beginning to understand how our brain develops, and how we learn,” Abel says. “These studies are promising for our ability to treat neurodevelopmental and neurodegenerative conditions.”

In addition to Abel, the research team included Vincent Luczak, a former graduate student in Abel’s lab, and Philipp Mews, a former graduate student in the University of Pennsylvania lab of Shelley Berger, the study’s senior author. The research was funded in part by grants from the National Institute for Mental Health.

Eric Taylor, UI assistant professor of biochemistry whose research focuses on cellular metabolism, notes that the thousands of pathways involved in cellular metabolism function as rivers of both information and energy. In some places many pathways come together, at a confluence. Acetyl-CoA is special because it sits at a confluence, and thus combines information and energy from several metabolic pathways.

“Dr. Abel’s and Berger’s work is groundbreaking because it provides a link among cognitive information processing and the flow of dynamic cellular information through metabolism, to a more stable form of cellular information in chromatin modification, and memory,” says Taylor, who was not involved in the study. “Their work showed that one pathway for generating acetyl-CoA, that flows through the protein Acetyl-CoA synthetase in the nucleus, is important for memory in the hippocampus. Key questions for future studies include whether other acetyl-CoA producing pathways are also important for memory, and if so, in what contexts and brain regions.”

(Full original article: The Loop)