Synaptic transmission: Diffusion to speed up recovery

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AMPARs ( alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors) recover from postsynaptic depression – receptor desensitization following stimulation – partly by lateral membrane diffusion and the exchange of desensitized receptors for 'fresh' ones.

Fast, repetitive synaptic stimulation wears a neuron out. The decrease in response to neurotransmitter that ensues, known as postsynaptic depression, is typically attributed to receptor desensitization. Heine and colleagues now show that the recovery of AMPARs ( alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors) from postsynaptic depression does not depend solely on receptor kinetics and neurotransmitter-clearance mechanisms, but also on lateral membrane diffusion.

By using fluorescence recovery after photobleaching (FRAP) and single quantum dots (fluorescent nanocrystals of semiconductor material) in cultured neurons and brain slices, the authors showed that AMPARs diffuse rapidly on the surface of neurons and are continuously exchanged between synaptic and extrasynaptic sites. Moreover, this mobility contributed to the recovery from postsynaptic depression: cross-linking AMPARs with antibodies reduced the amplitude of the second of two successive evoked excitatory postsynaptic currents (EPSCs), as well as the response to direct, local application of glutamate, compared with cells in which AMPARs were not immobilized.

To determine the respective contributions of receptor mobility and resensitization to postsynaptic depression recovery, the authors examined clustered and diffuse GluR1-containing AMPARs. Synapses with clustered GluR1-containing AMPARs displayed much stronger depression than those with diffuse receptors, even in the presence of cross-linking antibodies, suggesting that recovery is dominated by diffusion when mobility is high but that receptor kinetics are particularly influential when mobility is restricted.

This finding highlights the importance of endogenous mechanisms that regulate receptor mobility on recovery from postsynaptic depression and, hence, synaptic transmission. Indeed, the authors showed that increases in intracellular Ca²⁺, induced by activating NMDARs (N-methyl-D-aspartate receptors), reduced AMPAR mobility and slowed postsynaptic depression recovery.

Although receptor diffusion is known to be implicated in receptor turnover and neurotransmission on the second-to-minute timescale, this study demonstrates its contribution to the regulation of synaptic transmission in the millisecond time range. Based on the rates of mobility observed, 30% of the receptors at a synapse could be replaced within 10 ms — this exchange of desensitized receptors with 'fresh' ones from within the synapse or from extrasynaptic sites could be crucial to sustain fast excitatory synaptic transmission.

Monica Hoyos Flight

References

Heine, M. et al. Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320, 201–205 (2008) | Article | PubMed |