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Neurons constantly rewrite their DNA

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Scientists at the Johns Hopkins University School of Medicine have made a startling discovery about neurons. The details of the study have been published online in the journal Nature Neuroscience recently. It reveals that neurons are inherently risk takers and that they use minor DNA surgeries to toggle their activity levels all day. These activities have a tremendous significance in learning, memory and brain disorders, so the scientists are hopeful that this finding will give them insights on a number of vital questions.

Hongjun Song, Ph.D., a professor of neurology and neuroscience in the Johns Hopkins University School of Medicine’s Institute for Cell Engineering said that it was long believed in the scientific community that once a cell reaches its full maturation, a DNA is totally stable “ this includes all the molecular tags that are attached to it to control its genes and maintain the cell identity. However, with the finding of this research it has been revealed that some cells do alter their DNA to perform their everyday tasks, all the time.

The process of DNA alteration is known as demethylation. Methyl groups are actually regulatory tags that are tied to cytosines “ the C's in DNA's 4 letter alphabets. In order to remove them a multistep process need to be followed which requires excising a tagged cytosine from the long string of paired letters that form the chromosome. It should be ideally replaced with an untagged cytosine. Since, the process needs a cut to be made in the DNA, it can increase the chances of mutation in the DNA and that is the reason why it is sparing used by most cells. However, the recent studies have revealed something not known before “ it says that the mammals' brain exhibit a highly dynamic DNA modification activity. The research team of Song was curious to find out why such a risky process was going on in such a critical part of the brain.

Neurons communicate with other neurons through connections called synapses. At each synapse the initiating neuron releases chemical messengers that are intercepted by the receptor protein on the receiving neuron. Neurons are capable of toggling the volume of the communication by adjusting the activity levels of their genes. Songs team experimented by adding various drugs to neurons taken from the mouse brains and found that their synaptic activity went up and down accordingly. When the synaptic activity was up, so was the activity of the Tet3 gene, which kicks off DNA demethylation. When it was down, Tet3 was down too.

The then conducted the experiment other way round and manipulated the levels of T3 in the cells. To their surprise they found that when Tet3 levels were up, synaptic activity was down; when Tet3 levels were down, synaptic activity was up. Now the question arises whether the Tet3 levels depend on synaptic activity, or vice versa?

Through another series of experiments they found that one of the changes occurring in neurons in response to low levels of Tet3 was an increase in the protein GluR1 at their synapses. GluR1 is a receptor for chemical messengers, and its abundance at synapses is one of the ways neurons can toggle their synaptic activity.

They found that when the synaptic activity increases, Tet3 activity and base excision of tagged cytosines increases. This leads to the decrease in levels of GluR1 at synapses, which in turn decreases their overall strength and brings the synapses back to their previous activity level. It can also work the other way round. So, the crux is Tet3 levels respond to synaptic activity levels, and synaptic activity levels respond to Tet3 levels.

Song said that if we shut off neural activity, the neurons will try to get back to their usual level and vice versa. However, they cannot do it without Tet3. The ability to regulate synapse activity is the most fundamental property of neurons: Since this synaptic flexibility need mildly risky DNA surgery to work, it is possible that some brain disorders occur when neurons lose their ability to “heal” properly after base excision. Further studies can confirm this hypothesis.