Neurons Break Their Own DNA to Enable Memory Formation

Every time you learn something new, your brain cells fracture their DNA, creating deterioration that the neurons must immediately repair, according to a new study by researchers at MIT. It might seem that damaging your DNA is not a good thing, but this study flips that notion around, with the finding that this process is essential to learning and memory.

The results may eventually help researchers come up with new approaches to preventing cognitive decline in disorders such as Alzheimer’s disease.

Li-Huei Tsai, the Picower Professor of Neuroscience and director of the Picower Institute for Learning and Memory at MIT, said:

“Cells physiologically break their DNA to allow certain important genes to be expressed. In the case of neurons, they need to break their DNA to enable the expression of early response genes, which ultimately pave the way for the transcriptional program that supports learning and memory, and many other behaviors.”

The ability of the cells in your body to repair this DNA damage weakens however, as you age, which leads in turn to degeneration, Tsai says.

“When we are young, our brains create DNA breaks as we learn new things, but our cells are absolutely on top of this and can quickly repair the damage to maintain the functionality of the system. But during aging, and particularly with some genetic conditions, the efficiency of the DNA repair system is compromised, leading to the accumulation of damage, and in our view this could be very detrimental.”

Double Strand Breaks

The researchers found in earlier studies, looking into Alzheimer’s disease in mice, that even in the pre-symptomatic phase of the disorder, neurons in the hippocampal region of the brain contain a large number of DNA lesions, known as double strand breaks.

To more deeply investigate the potential consequences of such damage, the researchers studied what would happen if they created such damage in neurons. They applied a toxic agent to the neurons known to induce double strand breaks, and then harvested the RNA from the cells for sequencing.

As described in their paper in Cell, they found that while the vast majority had reduced expression levels, as expected, there was something surprising. Out of the 700 genes that showed changes as a result of the damage, 2 genes showed increased expression levels following the double strand breaks.

Importantly, these genes were known to be those which respond rapidly to neuronal stimulation, for example, a new sensory experience.

To find out if such breaks happen naturally during neuronal stimulation, the researchers next applied to the neurons a substance that causes synapses to strengthen in a similar way to exposure to a new experience.

“Sure enough, we found that the treatment very rapidly increased the expression of those early response genes, but it also caused DNA double strand breaks,” Tsai says.

Topoisomerase IIβ

How are these breaks linked with the apparent boost in early-response gene expression?

Following a computer analysis of the DNA sequences neighboring these genes, an enzyme known as topoisomerase IIβ was found to be responsible for the DNA breaks in response to stimulation.

They also studied the DNA sequences near these genes and discovered that they were enriched with a motif, or sequence pattern, for binding to a protein called CTCF. This “architectural” protein is known to create loops or bends in DNA.

In the early-response genes, the bends created by this protein act as a barrier that prevents different elements of DNA from interacting with each other — a crucial step in the genes’ expression.

The double strand breaks created by the cells allow them to collapse this barrier, and enable the early response genes to be expressed, Tsai says.

The findings have implications for our understanding of gene regulation. In addition, previous research has shown that aging is associated with a decline in the expression of genes involved in the processes of learning and memory formation.

Bruce Yankner, a professor of genetics and neurology at Harvard Medical School who was not involved in the research, said:

“The work elegantly links DNA strand break formation by the enzyme topoisomerase IIβ to the temporal control of transcription, providing the most compelling evidence to date that this is a core transcriptional control mechanism. I anticipate that this advance will have broad implications ranging from the basic biology of transcription to pathological mechanisms involved in diseases such as Alzheimer’s disease.”

Ram Madabhushi, et al.
Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes