Durham, NC, USA. As a newborn switches from amniotic fluid to breathing air, a profound shift occurs: the brain's nerve cells convert from hyperexcitability to a calm frame against which outside signals can be detected.

Fetal neurons need hyperexcitability for proper development, because they are moving to the correct brain locations and forming the right connections, but at birth, the brain undergoes a developmental shift. It controls a "pump" that drains chloride out of newborn neurons, quieting down these highly chaotic cells. The chloride shift is a a fundamental mechanism for brain function that changes newborn neurons and sets the stage for cognition.

Researchers at Duke University Medical Center used rodent models to study the genetic controls over the pump, discovering 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. Their findings appear in the Journal of Neuroscience.

Wolfgang Liedtke, M.D., Ph.D., assistant professor at the Duke Center for Translational Neuroscience and Klingenstein Fellow, worked with lead author Michelle Yeo, Ph.D., and colleagues to identify a set of DNA repressor elements that act as a pair of brakes.

Together the two repressors 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 the journal Science.

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."

CitationNovel Repression of Kcc2 Transcription by REST–RE-1 Controls Developmental Switch in Neuronal Chloride. Michele Yeo, Ken Berglund, George Augustine, and Wolfgang Liedtke. Journal of Neuroscience, 2009; 29(46): 14652-14662; doi: 10.1523/JNEUROSCI.2934-09.2009
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Abstract

Transcriptional upregulation of Kcc2b, the gene variant encoding the major isoform of the KCC2 chloride transporter, underlies a rapid perinatal decrease in intraneuronal chloride concentration (chloride shift), which is necessary for GABA to act inhibitory. Here we identify a novel repressor element-1 (RE-1) site in the 5' regulatory region of Kcc2b. In primary cortical neurons, which recapitulate the chloride shift in culture, the novel upstream RE-1 together with a known intronic RE-1 site function in concerted interaction to suppress Kcc2b transcription. With critical relevance for the chloride shift, only in the presence of the dual RE-1 site could inhibition of REST upregulate Kcc2b transcription. For this, we confirmed increased KCC2 protein expression and decreased intraneuronal chloride. Kcc2b developmental upregulation was potentiated by BDNF application, which was fully dependent on the presence of dual RE-1. In addition, the developmental chloride shift and GABA switch, from excitatory to inhibitory action, was accelerated by REST inhibition and slowed by REST overexpression. These results identify the REST–dual RE-1 interaction as a novel mechanism of transcriptional Kcc2b upregulation that significantly contributes to the ontogenetic shift in chloride concentration and GABA action in cortical neurons, which is fundamental for brain function in health and disease. Thus, we present here a new logic for the perinatal chloride shift, which is critical for establishment of GABAergic cortical inhibitory neurotransmission.

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