Tet3, which induces DNA methylation, serves as a regulator of synaptic activity. Here, overexpression of Tet3 decreases glutamatergic synaptic transmission (orange) in mouse hippocampal neurons. [Huimei Yu, Johns Hopkins Medicine]
Tet3, which induces DNA methylation, serves as a regulator of synaptic activity. Here, overexpression of Tet3 decreases glutamatergic synaptic transmission (orange) in mouse hippocampal neurons. [Huimei Yu, Johns Hopkins Medicine]

Managing the flow of information along the brain’s “wires” is a high-wire act. It depends on constant fine adjustments of the methylation marks in neuronal DNA. Such adjustments are inherently risky, but neurons wouldn’t be neurons without them. That is, neurons must dynamically regulate synapse activity if they are to enable everyday functions such as learning and remembering.

Removing methyl groups from DNA is a multistep process that requires excising a tagged cytosine from the long string of paired “letters” that make up a chromosome and, ideally, replacing it with an untagged cytosine. Because the process involves making a cut into DNA, it leaves the DNA somewhat vulnerable to mutations, so most cells use the process sparingly, mostly for correcting errors.

Recent studies, however, have turned up evidence that mammals' brains exhibit highly dynamic DNA modification activity, more than in any other area of the body. Why should the brain—such vital tissue—depend on such risky DNA renovations? The question intrigued a team of researchers at Johns Hopkins University.

The team, led by Hongjun Song, Ph.D., looked at the error-correction machinery neurons use to rework their DNA methylation marks. In particular, the investigators scrutinized the Tet family proteins, which oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. The investigators described their work April 27 in Nature Neuroscience, in an article entitled, “Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair.”

“We found that synaptic activity bi-directionally regulates neuronal Tet3 expression,” the authors wrote. “Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity.”

Dr. Song’s team also conducted a series of experiments that yielded a mechanistic insight: Tet3 can dictate neuronal surface GluR1 levels. For example, low levels of Tet3 can prompt neurons to increase 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.

The team used RNA-seq analyses to clarify Tet3's role in regulating gene expression in response to global synaptic activity. If synaptic activity increases, Tet3 activity and base excision of tagged cytosines increases. This causes the levels of GluR1 at synapses to decrease, in turn, which decreases their overall strength, 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.

The scientists assert they have discovered another mechanism used by neurons to maintain relatively consistent levels of synaptic activity so that neurons can remain responsive to the signaling around them. “If you shut off neural activity,” said Dr. Song, “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.”

Dr. 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, Dr. 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.

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