Researchers find link between estrogen, brain structure changes
March. 17, 2003
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."
Rockefeller University
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