Protein Facilitates Hard-Wiring of Brain Circuitry

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Brain

A mechanism underlying the molecular switch that turns young, adaptable brains into older, less malleable brains has been discovered by an international team of researchers led by a Duke University Medical Center neurobiologist.

The researchers discovered how neurons switch between neurotransmitter receptors during early brain development. This molecular switch signals the end of a critical period of brain "plasticity" in which simple sensory experiences, such as a mother's touch on the skin, are required to "wire" the brain appropriately. The researchers describe a key role for a neurotransmitter receptor called NR3A that is abundant in the brain for only a few weeks following birth.

According to the researchers, their findings could lead to a better understanding of disorders of early brain development. NR3A levels have been reported to be elevated in patients with schizophrenia, which is thought to be caused by subtle alterations of brain circuitry during development, said the scientists.

The team's results appeared this week in the advance online edition of Nature Neuroscience and will be published in an upcoming print issue of the journal. The work was supported by the National Institutes of Health, the American Heart Association, the Raymond and Beverley Sackler Foundation and the Ruth K. Broad Foundation.

"There is really no other neurotransmitter receptor that displays such a sharp and striking timing of expression in the brain," said the senior author of the study Michael D. Ehlers, M.D., Ph.D., Associate Professor of Neurobiology and Investigator of the Howard Hughes Medical Institute.

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Neurotransmitter receptors are molecules in the membranes of neurons that are activated by chemical signals sent from one neuron to another. The connection between neurons sending the signals and those receiving them is called the synapse. NR3A is a subunit of a molecule called the NMDA-type glutamate receptor, a neurotransmitter receptor required for most forms of learning and memory.

In order to investigate the switch between neurotransmitter receptors during development, Ehlers and his colleagues used fluorescent labels to follow the movement of NMDA receptors in the synaptic regions of rat neurons grown in culture. His studies revealed that receptors containing NR3A are much more rapidly removed from the synaptic surface of neurons than are receptors that lack NR3A, and this rapid disappearance enables them to be replaced by more 'mature' receptors.

The rapid removal of NR3A is mediated by the binding of a previously identified protein called PACSIN1, Ehlers said. This protein binds NR3A and drags NR3A receptors into the cell interior through a process known as endocytosis.

"From our findings, we postulate that PACSIN1 drives the removal of this very special class of NMDA receptors at a very specific time of brain development, allowing for the stabilization of synapse properties that produces more 'hard-wired' brain circuitry," Ehlers said.

According to Ehlers, the team's experiments could provide insight into disorders where the brain is wired incorrectly.

"NMDA receptor dysfunction has been implicated in diseases ranging from schizophrenia and stroke to drug addiction and Alzheimer's disease," Ehlers said. "Our results highlight the importance of this poorly studied NR3A receptor in brain development. I would not be surprised if this receptor plays an important role in several mysterious disorders of early brain development, such as schizophrenia or autism."

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