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DURHAM, N.C. -- Neurobiologists have pinpointed the
molecular storehouse that supplies the neurotransmitter
receptor proteins used for learning-related changes in the
brain. They also found hints that the same storage
compartments, called recycling endosomes, might be more general
transporters for 'memory molecules' used to remodel the neuron
to strengthen its connections with its neighbors.

They said their finding constitutes an important step toward
understanding the machinery by which neurons alter their
connections to establish preferred signaling pathways in the
process of laying down new memories.

Understanding such machinery could also offer clues to how
it might degenerate in aging and disease to degrade learning
and memory, they said

The researchers, led by Michael Ehlers of the Duke
University Medical Center and Julie Kauer of Brown University,
published their findings in the September 24, 2004, issue of
the journal Science. Other co-authors on the paper were
Mikyoung Park of Duke, and Esther Penick, Jeffrey Edwards of
Brown. Their research was supported by the National Institutes
of Health.

In their studies, the researches sought to understand how
neurotransmitter receptors in the depths of the neuron are
carried to the surface -- a process called exocytosis. These
receptors are proteins that are activated by bursts of
signaling chemicals, called neurotransmitters, launched from
another, transmitting neuron. The connection between
transmitting and receiving neurons is called the synapse.

Such activation across the synapse triggers a nerve impulse
in the receiving neuron. The "receiving stations" for
neurotransmitters are mushroom-shaped dendritic spines that
festoon the surface of neurons.

Changes in the strength of a neuron's response to such
chemical signals depend on how many receptors are present on
the dendritic spine surface. And the strength of such
connections is key to establishing the neural pathways through
the brain that are the basis of learning and memory.

The particular receptors that the researchers studied are
AMPA receptors, named for the chemical substance that activates
them. When the number of receptors on a neuronal surface
increases, the enhanced sensitivity of neurons to
neurotransmitter signaling is known as long-term potentiation
(LTP)

"There had been good evidence that the increase in receptor
number was due to exocytosis and that AMPA receptors were
coming from somewhere inside the neuron," said Ehlers. "But it
was completely unknown what that intracellular source or
compartment was."

The candidates for such transport included several different
kinds of sac-like carriers called endosomes and vesicles, which
are known to enclose and transport various molecular cargos in
the cell. Depending on the type of carrier, the cargo may be
carried to cellular "garbage dumps" where they are destroyed,
or recycled back to the cell surface.

"We knew that endosomes existed near dendritic spines and
that AMPA receptors get internalized and transported through
various endosomal compartments in dendrites," said Ehlers.
Finally, he said, the movement of AMPA receptors had to be
regulated by activation by yet another receptor, called the
NMDA receptor, that is known to trigger LTP in neurons.

In their studies, the researchers concentrated particularly
on "recycling endosomes" that transport "used" receptors back
to the neuronal surface after they have been drawn into the
neuron. To study the function of recycling endosomes, they
introduced mutations in cultured rat neurons and in brain
tissue that specifically disrupted transport of cargo in and
out of recycling endosomes.

They found that this disruption specifically trapped AMPA
receptors in the recycling endosomes. Also, the mutations
specifically prevented the insertion of new AMPA receptors into
the dendritic membrane. And, it specifically blocked the
insertion of receptors that would be triggered by NMDA
activation -- meaning that it affected long-term
potentiation.

To their surprise, the researchers also found that
triggering LTP not only affected insertion of AMPA receptors,
but the generalized recycling of molecular cargo to the
dendritic surface.

"We've always concentrated on AMPA receptors because they
were easy to measure," said Ehlers. "But we wondered whether
there is more to membrane trafficking during LTP than just AMPA
receptors. After the initial stimulus that triggers insertion
of AMPA receptors, there is overall spine growth and changes in
synaptic structure and architecture. But the link between the
activating stimulus and the spine changes has been a mystery.
So, we thought that if recycling endosomes were supplying
receptors, perhaps they're supplying additional components for
spine growth," he said.

When the researchers stimulated LTP in the brain slices,
they found an overall enhancement of transport of cargo from
recycling endosomes to the neuronal membrane.

"We think it's a key point that when you provide an
LTP-inducing stimulus, you get an enhanced recycling not just
of AMPA receptors but of all recycling cargo," said Ehlers.
"So, it seems to be a mechanism that's operating on a specific
organelle -- the recycling endosome -- rather than on a
specific molecule, the AMPA receptor. So, it will be an
intriguing question to ask, what other cargo molecules are
mobilized during LTP."

Thus, said Ehlers, the machinery of the recycling endosome "
is a very appealing unifying mechanism for the various forms of
plasticity."

"Researchers have been rather daunted by the fact there is a
diversity of molecules and mechanisms involved in LTP. And
they've wondered if there was any way to find a convergence
point to explain how they all control the single outcome of
LTP. So, while there may be hundreds of molecules, there may be
just one organelle -- the recycling endosome -- involved in
transporting them. Our findings hint that this endosome might
just provide the convergence point for understanding LTP," he
said.

Besides basic understanding of LTP, such studies could have
important clinical implications, said Ehlers.

"Aging and neurodegeneration has been associated with
enlarged and expanded endosomes in neuronal dendrites," said
Ehlers. "It's been unclear how this happens or its functional
effect.

"And there's been an association of aging and
neurodegeneration with altered synaptic function and
plasticity. So, there may be a link between an endosomal
dysfunction and aberrant synaptic plasticity that happens later
in life," he said.

"Identifying recycling endosomes as a source of receptors
and other plasticity proteins opens up new possibilities for
therapeutic approaches to diseases of memory and cognition,"
said Ehlers.