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Protein Facilitates "Hard-Wiring" of Brain Circuitry

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Duke Health News 919-660-1306

DURHAM, N.C. -- 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.

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. Their
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."

Collaborators on the study include Isabel Pérez-Otaňo of the
University of Navarra; Rafael Lujan of the University of
Castilla-La Mancha; Steve J. Tavalin of the University of
Tennessee; Markus Plomann and Jan Modregger of the University
of Cologne; Xia-Bo Liu and Edward G. Jones of the University of
California, Davis; Stephen F. Heinemann of the Salk Institute;
and Donald C. Lo of Duke University.

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