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Glutamate receptors on the move

Naturevolume 417pages601602 (2002) | Download Citation

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Receptors for the neurotransmitter glutamate are more mobile than previously suspected. They meander about on the neuronal surface and become reversibly trapped at the junctions between neurons.

Neurons communicate with each other at specialized junctions known as synapses. In excitatory synapses of the brain, a signal-transmitting (presynaptic) neuron secretes glutamate — a chemical messenger that diffuses across the synaptic 'cleft' to bind to glutamate receptors concentrated in the postsynaptic membrane of the receiving neuron. A major subtype of glutamate receptor, the AMPA receptor, contains an ion channel that opens when glutamate binds to it, causing excitation of the post-synaptic neuron. The abundance of AMPA receptors in the postsynaptic membrane controls the magnitude of postsynaptic excitation and is a major factor in determining the strength of synaptic transmission. So it is clearly important to understand how these receptors accumulate in synapses. On page 649 of this issue, Borgdorff and Choquet1 reveal an unexpected dynamic behaviour of AMPA receptors (Fig. 1). Remarkably, the receptors wander around rapidly on the surface of neurons, stopping temporarily when they approach synapses. More interestingly, this 'lateral' mobility of AMPA receptors is controlled by signals that are known to regulate synaptic strength.

Figure 1: Wandering receptors.
Figure 1

AMPA receptors, a subtype of receptor for the neurotransmitter glutamate, are found in postsynaptic neurons; they are ion channels that open in response to glutamate, which is released from presynaptic neurons. AMPA receptors can move between an intracellular pool and the neuronal surface, by the processes of exocytosis and endocytosis. As Borgdorff and Choquet1 show, the receptors can also move by lateral diffusion in the plasma membrane until they are captured and immobilized by putative anchoring proteins concentrated in postsynaptic regions. AMPA receptors are also immobilized by increases in intracellular calcium levels, perhaps after calcium influx through postsynaptic calcium channels.

Modulation of the number of postsynaptic AMPA receptors is a potent mechanism used by neurons to change synaptic strength2,3,4. The resulting levels of AMPA receptors can be stable over long periods, so such a mechanism also offers a way to store information and memories in the brain. For these reasons, there is great interest in the dynamic distribution of AMPA receptors in neurons, particularly in how the receptors are delivered to synapses (leading to synaptic potentiation) and how they are removed (producing synaptic depression).

How can one study the dynamics of native AMPA receptors in neurons? The receptors alone are too small to see, even with a microscope, so Borgdorff and Choquet1 coated tiny latex beads with antibodies that bind to the receptors. When applied to living neurons in culture, the beads adhere to AMPA receptors on the neuronal surface and act as microscopic signposts. In this way, lateral movements of the receptors can be tracked by video microscopy.

Using this approach, Borgdorff and Choquet found that AMPA receptors alternate abruptly between periods of rapid meandering (probably diffusion) on the neuronal outer membrane and periods of restricted motion within a submicrometre area ('confinement'). Confinement occurred mostly when the receptors were near synapses (which were detected with a specific dye). These findings imply that a zone of restricted diffusion exists in the neighbourhood of synapses. This 'perisynaptic' region probably contains specific anchoring proteins that bind to and tether AMPA receptors. The beads are too big to penetrate the narrow synaptic cleft, so a drawback of the approach is that it cannot sample true synaptic receptors. So we are left to presume that AMPA receptors located actually within the synapse are, like the peri-synaptic receptors, also immobile.

Borgdorff and Choquet also observed that AMPA receptors sometimes moved from the vicinity of one dye-stained synaptic region to another. Whether this occurs in vivo is unclear. Normally, surface AMPA receptors undergo internalization (endocytosis), in which a patch of receptor-containing membrane is pinched off into the neuron as a tiny sac. Internalized receptors are then recycled back to the surface by secretion (exocytosis), in which the internal sacs fuse with the plasma membrane5,6. The attachment of a latex bead to surface AMPA receptors is expected to prevent endocytosis; indeed, the authors found that abortive endocytosis seemed to account for a small minority of confinements. So perhaps the propensity to move from one synaptic region to another is exaggerated by the prolonged lifetime of bead-attached AMPA receptors on the neuronal surface.

More significantly, Borgdorff and Choquet showed that the surface mobility of AMPA receptors is influenced by intracellular calcium ions. The authors evoked a localized increase in calcium concentration in neurons by using a laser beam. In response, nearby AMPA receptors rapidly became immobilized, and this immobility persisted after the calcium spike. As postsynaptic calcium increases are a cardinal feature of excitatory synaptic transmission, calcium-dependent immobilization might explain why AMPA receptors accumulate at synapses. A large postsynaptic increase in calcium concentration is also a well-known signal for strengthening of synapses, so, more interestingly, this could also be a mechanism for gathering more AMPA receptors in synapses to potentiate the postsynaptic response. Indeed, Borgdorff and Choquet observed that repeated calcium increases led to a local accumulation of AMPA receptors on the neuronal surface. But it remains to be seen whether surface AMPA receptors accumulate in response to postsynaptic calcium increases under more 'natural' conditions — that is, after synaptic stimulation.

Until now this field has focused on the idea that the delivery of AMPA receptors to synapses is regulated by exocytosis from internal compartments in the neuron6,7. The study by Borgdorff and Choquet1 points to another possibility, involving the lateral movement of surface receptors from extrasynaptic sites. The idea is supported by an earlier study of a mouse mutant called Stargazer, which shows neurological defects8. This study suggested that a critical step in synaptic delivery occurs after AMPA receptors reach the cell surface. More recently, another major subtype of glutamate receptor, the NMDA receptor, has been shown to move laterally from extrasynaptic to synaptic sites9. So a dynamic surface distribution might be a universal property of synaptic receptors.

What molecular mechanisms underlie the controlled lateral mobility of AMPA receptors? Presumably, it has something to do with calcium-regulated interactions between the receptors and intracellular anchoring proteins. More generally, how do synapses and synaptic circuits in the brain maintain consistent properties in the face of such molecular flux (assuming that it occurs in vivo)? The answer to this question is a long way off, but it is clear that the more we probe the molecular workings of synapses, the more we can understand their dynamic organization and their readiness for rapid change.

References

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    Borgdorff, A. J. & Choquet, D. Nature 417, 649–653 (2002).

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    Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Nature Rev. Neurosci. 2, 315–324 (2001).

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    Ehlers, M. D. Neuron 28, 511–525 (2000).

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    Passafaro, M., Piech, V. & Sheng, M. Nature Neurosci. 4, 917–926 (2001).

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    Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Cell 105, 331–343 (2001).

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    Chen, L. et al. Nature 408, 936–943 (2000).

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    Tovar, K. R. & Westbrook, G. L. Neuron 34, 255–264 (2002).

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  1. the Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    • Morgan Sheng
    •  & Terunaga Nakagawa

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https://doi.org/10.1038/417601a

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