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.
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