New 'Shuttle' Mechanism Discovered by Which Nerve Cells' Connections are Altered
DURHAM, N.C. -- In the process of strengthening or weakening their interconnections, brain cells use a "shuttle" system to increase or decrease the number of receptors for a key signal-transmitting chemical, a Duke University Medical Center neurobiologist has discovered.
Such control of connection strength is critical to the processes of establishing preferred neural pathways, the basis of learning and memory in the brain. The discovery not only offers new insight into how the brain manages the strength of its connections, but also potential targets for drugs to treat stroke, epilepsy and neurodegenerative disease, said Michael Ehlers, assistant professor of neurobiology.
In an article in the Nov. 22 edition of Neuron, Ehlers reports that neurons control their sensitivity to the neurotransmitter glutamate by removing or inserting receptors for glutamate from the "post-synaptic membrane" - the point on a neuron at which it receives neurotransmitter signals launched from a neighboring neuron.
According to Ehlers, scientists have long known that one neuron triggers a nerve impulse in another by chemical communications at connections between neurons called synapses. In this process, one neuron launches a burst of chemical neurotransmitters such as glutamate from a "pre-synaptic membrane" across a gap between the cells called the synaptic cleft. When this neurotransmitter burst reaches the target neuron's post-synaptic membrane, it binds to molecular switches known as receptors, triggering the firing of a nerve impulse in the receiving neuron. In the case of glutamate, a neurotransmitter found in more than half the synapses in the brain, one key receptor is known as the AMPA receptor.
"There has been some controversy over whether this strengthening or weakening involved a pre-synaptic or post-synaptic change," Ehlers said. "And one of the possibilities for post-synaptic change was a change in the AMPA receptors. While one theory was that the receptors were somehow made more active, a relatively recent idea was that a neuron's responsiveness could be regulated by changes in the number of receptors in the membrane available to bind glutamate."
Strengthening of such neural connections is known as long-term potentiation (LTP), and weakening the connection is known as long-term depression (LTD), said Ehlers. While LTP and LTD represent changes in connection strength that occur rapidly, he explained, neurons also undergo slower adjustments in their connection strength.
"So there are these two competing modes of neuronal plasticity, if you will," said Ehlers. "And up until now, we had little idea of the cellular or molecular relationship between these two modes." Thus, in his experiments, Ehlers sought to understand both the rapid and slower forms of connection adjustment. He based his work on recent studies by other researchers that indicated that AMPA receptors seemed to be mobile, cycling in and out of the cell membrane.
To investigate these microscopic changes at nerve cell synapses, Ehlers used various tracers to follow the movement of AMPA receptors in the synaptic regions of rat neurons grown in culture. His studies revealed that, after the receptors spend some time in the post-synaptic membrane, they are drawn back into the cell in a process called endocytosis, in which they are enveloped in a bubble-like vesicle. His experiments revealed that the rate of both this endocytosis and reinsertion of receptors depended on the firing activity of the neurons.
"Our studies revealed that in some cases, the receptors would recycle and return to the membrane, but if they received a different signal, they would be degraded," Ehlers said. "So, this system allows the neuron to very quickly decrease or increase the number of receptors in the membrane by controlling the rate of recycling. Also, by selectively shunting receptors either to return to the membrane or to be degraded, the neurons can more slowly regulate how many receptors they have at that synapse."
According to Ehlers, his experiments show that the regulation of AMPA receptors also appears to be related to the activity of yet another glutamate receptor, called the NMDA receptor that sits close to the AMPA receptor synaptic membranes.
"Interestingly, we found that activation of either AMPA receptors or NMDA receptors can both trigger the internalization of AMPA receptors," said Ehlers. "So, depending on the relative amount of activation of AMPA or NMDA receptors, the neuron can control whether or not it maintains its synapse by keeping receptors recycling back into it, or targets internalized receptors for degradation."
Ehlers and his colleagues plan to continue their work by exploring the regulatory signals that govern the system of managing receptor numbers. Such studies could have important medical implications, he said.
"If you could develop drugs that would, for example, augment recycling of these receptors, you might be able to prevent the weakening of synapses that occurs in neurodegenerative diseases or impaired memory states," he said. "On the other hand, drugs that shut off recycling and promote degradation would reduce receptor activity, and potentially be useful for treating epilepsy or strokes.
"Current drugs for many of these disorders, which bind to receptors to block their activation, have fairly bad side effects, but controlling the number of receptors might give us a finer level of therapeutic control - allowing a continuous scale of increasing or decreasing receptor activity," Ehlers said.
The research was supported by the National Institutes of Health and the Spinal Cord Research Foundation.