For a long time it has been thought that DNA in mature or terminally differentiated cells like neurons is static. But scientists from Johns Hopkins have proved this wrong. In their latest study, researchers observed that DNA in neurons undergo microsurgeries to toggle the everyday activities. Scientists refer to these microsurgeries which alter DNA as DNA demethylation. The DNA is the genetic molecule formed by a very organized combination of four nucleotides familiar as A, T, G and C. One of the nucleotides ‘C’ or cytosine is modified or permanently tagged with methyl groups.
Scientists observed that the DNA in neurons get altered all the time, getting demethylated to carry out daily activities of the cells and this determines the body’s behavior. This demethylation process involves a molecular microsurgery wherein the methylated ‘C’ is excised out of the double-stranded DNA molecule and replaced with an unmethylated ‘C’. This process makes the DNA vulnerable and prone to mutagenesis which could be lethal and inheritable. It is observed that of all the body cells, brain cells i.e. neurons exhibit this highly dynamic activity the most.
“We used to think that once a cell reaches full maturation, its DNA is totally stable, including the molecular tags attached to it to control its genes and maintain the cell’s identity,” says Hongjun Song, Ph.D., a professor of neurology and neuroscience in the Johns Hopkins University School of Medicine’s Institute for Cell Engineering. “This research shows that some cells actually alter their DNA all the time, just to perform everyday functions.”
Neurons communicate with each other through junctions called synapses, where the chemical message from initiating neuron is intercepted by the receptor proteins of the receptive neuron for effective signal transmission or communication. Neurons adjust their gene activity to regulate protein levels in accordance to the volume of communication. Song’s team observed that Tet3 gene activity was regulated in direct proportion to the communication volume which is synaptic activity in mouse neurons treated with different drugs. Tet3 is known to kick-off DNA demethylation. On the other hand, when Tet3 levels were manipulated in cells, surprisingly- Tet3 activity behaved inverse to that of the synaptic activity.
After a series of experiments to understand whether Tet3 levels depend on synaptic activity or not, scientists observed 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. Since GluR1 is a receptor for chemical messengers, its abundance at synapses is one of the ways neurons can toggle their synaptic activity.
Given the direct and inverse regulation of Tet3, scientists have discovered a mechanism by which neurons maintain consistent levels of synaptic activity and can remain responsive to the signaling around them. If synaptic activity increases, Tet3 activity and base excision of methylated cytosines increases. This causes the levels of GluR1 at synapses to decrease, in turn decreasing their overall strength and bringing the synapses back to their previous activity level. The opposite can also happen, resulting in increasing synaptic activity in response to an initial decrease. So Tet3 levels respond to synaptic activity levels, and synaptic activity levels respond to Tet3 levels.
Song says: “If you shut off neural activity, the neurons ‘turn up their volume’ to try to get back to their usual level and vice versa. But they can’t do it without Tet3.”
Song adds that the ability to regulate synapse activity is the most fundamental property of neurons: “It’s how our brains form circuits that contain information.” Since this synaptic flexibility seems to require mildly risky DNA surgery to work, Song wonders if some brain disorders might arise from neurons losing their ability to “heal” properly after base excision. He thinks this study brings us one step closer to finding out.
The study was funded by and published in the journal Nature Neuroscience.