"Rockefeller,
Weill Cornell researchers find link between estrogen, brain structure changes"
Scientists at
Rockefeller University and Weill Medical College of Cornell University
have discovered how estrogen initiates physical changes in rodent brain
cells that lead to increased learning and memory -- a finding, the researchers
contend, that illustrates the likely value of the hormone to enhance brain
functioning in women.
Their study, published
in the March 15 issue of The Journal of Neuroscience, describes for the
first time a chain of molecular events that is activated in the brain's
primary memory center, called the hippocampus, when estrogen bathes neurons
(nerve cells).
The study details
how these nerve cells "grow in complexity" when exposed to estrogen, increasing
connections among nerve cells in an area of the brain needed to store new
memories, retrieve older ones and even recall location of an object or
event in space.
A second study, published
in the same journal by Weill Cornell Medical College scientists, led by
Teresa Milner, Ph.D., in collaboration with Rockefeller University investigators,
finds the same results in animal tissue experiments. Both the first study,
at the test tube level, and the Milner tissue study were conducted simultaneously
but independently, and serve as sort of "blind controls" in support of
each other.
"We found a novel
way in which estrogen affects neuronal structural remodeling in the hippocampus,"
says paper co-author Bruce S. McEwen, Ph.D., Professor and head of the
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at
Rockefeller University.
"It shows us that
estrogen plays an unsuspected role in primary biological processes involved
in strengthening normal learning and memory function," says McEwen.
"We observed the
neuronal structural remodeling at the subcellular level through electron
microscopy," notes Milner, professor of neuroscience in the Division of
Neurobiology at Weill Cornell. "We were able to visualize precise changes
in protein distribution at the actual dendritic spines of the neurons."
Findings from several
previous studies have been mixed about whether estrogen replacement therapy
bolsters brain functioning in postmenopausal women. McEwen says that the
new study suggests some form of postmenopausal estrogen replacement may
indeed be both helpful and neuroprotective.
"Even without estrogen,
there are still plenty of synaptic connections in the hippocampus," McEwen
says. "The study suggests that without estrogen, the connections that are
there don't work as efficiently in storing and recalling certain types
of memories, such as word lists, or remembering where something is in space,"
he said. "The hope is that an estrogen mimic could be developed that protects
women not just against memory loss, but Alzheimer's disease, the consequences
of stroke and other brain disorders."
"Hormones like estrogens,
which circulate in the bloodstream, are a major part of the communication
system in the brain," McEwen concludes.
At its most fundamental,
the study solves several neurobiological mysteries that were seemingly
unrelated, says co-author Keith T. Akama, Ph.D., a postdoctoral researcher
in McEwen's laboratory. It answers the question of why estrogen receptors,
through which the hormone stimulates the cell, are located on the outer
reaches of the neurons-- an observation that many researchers have been
trying to explain --and it uncovers a functional role for protein synthesis
that occurs far away from the cell body near the synapses. Protein synthesis
is thought to be important in learning and memory.
"This marries two
schools of neurobiology together," Akama says. "Much was known within those
two separate investigative paths, but this experiment connected the dots,"
he says.
Estrogen at synapses
In earlier research
with rodents, Milner, together with the McEwen laboratory, had demonstrated
for the first time that estrogen receptors occur at the edges of nerve
cells in the CA1 region of the hippocampus, far away from the cell's nucleus
where most estrogen receptors are traditionally found. These receptors
at the edges of the cells are found on structures known as "dendritic spines"
-- the part of the cells that receives signals from other neurons in the
central nervous system.
From a nerve cell,
long tentacles called dendrites branch many times, extending out to reach
other neurons. Dendritic branch points are covered with the nub- or bump-like
spines, which are often the sites of synapses, junctions between neurons
that pass chemical messages. When the spines are activated, they grow,
or mature, into mushroom caps in order to make connections with the next
neuron.
McEwen and many other
scientists believe "plasticity," or the constant structural reshaping of
synapses in forming new dendritic spines, encodes processes necessary to
promote learning and memory. These spines are diminished in the aged
brain and are atrophied in Alzheimer's disease. Furthermore,
McEwen also believes that the formation of new spines may be a major way
by which the brain protects itself from damage such as trauma and stroke.
Plasticity also allows the brain to relearn skills that may have been lost
to injury -- such as by stroke -- by rewiring important functions via alternate
nervous system pathways.
Previous studies
in mammals by McEwen and others showed that low estrogen levels reduced
the animals' performance on learning and memory tests, but estrogen treatment
reversed this negative effect, thus providing a link between estrogen and
activity in the hippocampus. Human studies have also shown that the ability
of women to remember word lists and other experimental tasks varies during
a normal monthly estrous cycle, which is characterized by the ebb and flow
of estrogen.
Further animal investigation
revealed a dramatic decrease in dendritic spine density in rats whose ovaries
were removed and thus were relatively low in blood estrogen levels; however,
administering estrogen to the animals increased their spine formation.
McEwen and his colleagues also found that the density of synapses and synaptic
spines fluctuates during an animal's estrous cycle, increasing in response
to estrogen.
This new study is
the first to shed light on the precise molecular pathway by which estrogen
increased the "plasticity" of neuronal spines. In the study, McEwen and
Akama explored the question of how estrogen receptors influence growth
of dendritic spines.
"We know how estrogen
works genomically inside the cell's nucleus, how it turns on gene transcription,
producing proteins, which are then shipped to where they are needed," says
Akama. "But it is a long way from the nucleus to the synaptic ends of the
neuron, where changes occur very rapidly, so estrogen has also found a
way to work at edges of the nerve cell. We wanted to find out how."
Messenger RNA
hanging out
The researchers reasoned
that an increase in the number of spines requires the translation, or synthesis,
of new proteins, and they chose to investigate a key protein that has been
found near estrogen receptors at the spine with undefined regulation of
new protein synthesis.
That protein, postsynaptic
density-95 (PSD-95), is a structural protein that researchers believe plays
a critical role in building a synapse and maintaining plasticity.
"A lot of researchers
have looked at PSD-95, but it was not known to play any role with estrogen,"
says Akama. "Furthermore, no one knew how a neuron regulates PSD-95 production."
Through a series
of test tube experiments, Akama and McEwen were able to delineate the molecular
mechanisms by which estrogen might directly orchestrate such spine formation
and development of synapses.
They found that in
a neuronal cell line, estrogen binding to its receptor led to a series
of signaling switches that resulted in PSD-95 protein translation. These
switches involves rapid activation of an enzyme called Akt, a common intermediate
in signaling pathways, which subsequently disinhibits 4E-BP1 (eukaryotic
initiation factor-4E binding protein 1) to allow new protein synthesis.
"PSD-95 mRNA is hanging
out near the spines and was not being translated because it had a big,
inhibiting protein complex bound to it," says Akama. "Phosphorylation of
4E-BP1 disrupts this binding and when estrogen stimulates this release
of 4E-BP1, new PSD-95 proteins were rapidly synthesized. More PSD-95 protein
translated immediately at the spine increases spine maturation and synaptic
formation. All this action is occurring far away from the nucleus, way
off in the dendrite, without estrogen traveling back and forth down to
the nucleus.
"In addition to the
genomic mechanisms initiated within the nucleus, we have shown another
way that estrogen can regulate dendritic function, and this gives us hope
that selective agents can be developed that work through these signal pathways.
The study was funded
by grants from the National Institutes of Health and the Ares-Serono Foundation.
Founded by John D.
Rockefeller in 1901, The Rockefeller University was this nation's first
biomedical research university. Today it is internationally renowned for
research and graduate education in the biomedical sciences, chemistry,
bioinformatics and physics. A total of 22 scientists associated with the
university have received the Nobel Prize in medicine and physiology or
chemistry, 18 Rockefeller scientists have received Lasker Awards, five
have been named MacArthur Fellows, and 11 have garnered the National Medal
of Science. More than a third of the current faculty are elected members
of the National Academy of Sciences.
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