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Explanation for rapid maturation of neurons at birth

November 20, 2009
Duke University Medical Center
So a baby can detect outside signals, the brain cells use a a "pump" that drains chloride out of newborn neurons, making these highly chaotic, developing cells quiet down. Researchers have figured out the genetic control of the pump in rodents.

The figure shows a novel gene-regulatory mechanism of the neuronal chloride transporter, Kcc2, which is the only transporter that removes chloride molecules from cells. During mammalian development, chloride levels are high in neurons, but levels rapidly decrease around the time of birth when the Kcc2 transporter removes the chloride. Low neuronal chloride is the hallmark of virtually all mature central nervous system neurons. The study findings help us better understand the neurodevelopmental neuronal chloride shift at birth and form a basis for exploring chloride increases in neuronal injury. Researchers may focus on conditions like epilepsy and neuropathic pain to learn whether high chloride levels could be causing problems. The researchers have shown that binding of the REST transcriptional repressor complex to a unique binding element in the promoter portion of the Kcc2b gene works as a transcriptional dual-brake mechanism. Releasing the REST-complex "brake" leads to increased Kcc2b expression, which "pumps" out the chloride in mature neurons.
Credit: Image courtesy of Duke University Medical Center

At the moment a newborn switches from amniotic fluid to breathing air, another profound shift occurs: nerve cells in the brain convert from hyperexcitability to a calm frame against which outside signals can be detected.

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"Fetal neurons need hyperexcitability for proper development, because they are moving to the right places (in the brain) and forming the right connections," said Wolfgang Liedtke, M.D., Ph.D., assistant professor at the Duke Center for Translational Neuroscience and Klingenstein Fellow in Neuroscience. "But at birth, the brain has to undergo a developmental shift."

It does this by controlling a "pump" that drains chloride out of newborn neurons, making these highly chaotic, developing cells quiet down. Researchers at Duke University Medical Center have figured out the genetic control of the pump in rodents.

These findings may ultimately benefit people who suffer from the neuron misfirings that occur in epilepsy and neuropathic pain, Liedtke said.

"The "chloride shift" is a process that changes newborn neurons and sets the stage for cognition," said Liedtke, who is also an attending physician at Duke Pain Clinics. "It is a fundamental mechanism for brain function."

The findings were published online in the Journal of Neuroscience on Nov. 19.

The researchers discovered why the pump is almost absent in the developing brain and then goes into high gear after birth: there's a dual-brake mechanism that keeps the chloride-transporter (pump) molecules in check during pregnancy.

Liedtke, lead author Michelle Yeo, Ph.D., and the rest of the team identified a set of DNA repressor elements that act as a pair of brakes. Together the two suppress the gene Kcc2, which is responsible for producing proteins for the transporter molecules that "pump" out the chloride.

The researchers confirmed that increased activity of the gene resulted in lower levels of chloride in the neurons.

Around birth and for a few months afterward, when the brakes are no longer holding fast, Kcc2 makes proteins for the transporter molecules which remain at high levels for a lifetime.

What remains unknown is how the brakes, known as REST (Repressor Element Silencing Transcription) are turned off so Kcc2 can encode for the transporter proteins.

"The research was motivated by trying to understand how the Kcc2 levels are lowered in pathological states like chronic pain and epilepsy," said Yeo, who is a research scientist in the Duke Division of Neurology and author of a landmark study of REST in Science journal. The scientists wanted to create a developmental model that would explain how the pump functions. They also wanted to explore the hyperexcitability of neurons in people with chronic pain and epilepsy, and what makes their neurons revert to this earlier state.

Re-establishing natural inhibition in chronic pain and epilepsy may be a more rational, realistic approach to treatment, Yeo said.

Liedtke also noted that neuron maturation, in terms of the chloride shift, is faster in female rodents. "It's really true that girls mature faster than boys. In rodents, by the three-month mark after birth, there is no difference in chloride levels in neurons. The males catch up."

Other authors on the paper were Ken Berglund and George Augustine of the Duke Department of Neurobiology. This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke grant, a National Institute on Aging Pilot Project Grant, and grant support from the Mathers Foundation, the Esther A. and Joseph Klingenstein Fund, and startup funds from Duke University.

Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

  1. Michele Yeo, Ken Berglund, George Augustine, and Wolfgang Liedtke. Novel Repression of Kcc2 Transcription by REST-RE-1 Controls Developmental Switch in Neuronal Chloride. Journal of Neuroscience, 2009; 29 (46): 14652 DOI: 10.1523/JNEUROSCI.2934-09.2009

Cite This Page:

Duke University Medical Center. "Explanation for rapid maturation of neurons at birth." ScienceDaily. ScienceDaily, 20 November 2009. <www.sciencedaily.com/releases/2009/11/091117184531.htm>.
Duke University Medical Center. (2009, November 20). Explanation for rapid maturation of neurons at birth. ScienceDaily. Retrieved January 28, 2015 from www.sciencedaily.com/releases/2009/11/091117184531.htm
Duke University Medical Center. "Explanation for rapid maturation of neurons at birth." ScienceDaily. www.sciencedaily.com/releases/2009/11/091117184531.htm (accessed January 28, 2015).

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