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The Journal of Neuroscience, October 10, 2007, 27(41):11112-11121; doi:10.1523/JNEUROSCI.2465-07.2007

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Cellular/Molecular
Real-Time Imaging of Discrete Exocytic Events Mediating Surface Delivery of AMPA Receptors

Guillermo A. Yudowski,^1 * Manojkumar A. Puthenveedu,^1 * Dmitri Leonoudakis,⁴ Sandip Panicker,² Kurt S. Thorn,³ Eric C. Beattie,⁴ and Mark von Zastrow^1,2

Departments of ¹Psychiatry, ²Cellular and Molecular Pharmacology, and ³Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, and ⁴California Pacific Medical Center Research Institute, San Francisco, California 94107

Correspondence should be addressed to Mark von Zastrow, Room N212, Genentech Hall, University of California at San Francisco Mission Bay Campus, 600 16th Street, San Francisco, CA 94158-2140. Email: mark.vonzastrow{at}ucsf.edu

We directly resolved discrete exocytic fusion events mediating insertion of AMPA-type glutamate receptors (AMPARs) to the somatodendritic surface of rat hippocampal pyramidal neurons, in slice and dissociated cultures, using protein tagging with a pH-sensitive GFP (green fluorescent protein) variant and rapid (10 frames/s) fluorescence microscopy. AMPAR-containing exocytic events occurred under basal culture conditions in both the cell body and dendrites; potentiating chemical stimuli produced an NMDA receptor-dependent increase in the frequency of individual exocytic events. The number of AMPARs inserted per exocytic event, estimated using single-molecule analysis, was quite uniform but individual events differed significantly in kinetic properties affecting the subsequent surface distribution of receptors. "Transient" events, from which AMPARs dispersed laterally immediately after surface insertion, generated a pronounced but short-lived (dissipating within 1 s) increase in surface AMPAR fluorescence extending locally (2–5 µm) from the site of exocytosis. "Persistent" events, from which inserted AMPARs dispersed slowly (typically over 5–10 s), affected local surface receptor concentration to a much smaller degree. Both modes of exocytic insertion occurred throughout the dendritic shaft, but remarkably, neither mode of insertion was observed directly into synaptic spines. AMPARs entered spines preferentially from transient events occurring in the adjoining dendritic shaft, driven apparently by mass action and short-range lateral diffusion, and locally delivered AMPARs remained mostly in the mobile fraction. These results suggest a highly dynamic mechanism for both constitutive and activity-dependent surface delivery of AMPARs, mediated by kinetically distinct exocytic modes that differ in propensity to drive lateral entry of receptors to nearby synapses.

Key words: trafficking; glutamate; imaging; synapse; plasticity; exocytosis

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Received May 30, 2007; revised Aug. 23, 2007; accepted Aug. 26, 2007.

Correspondence should be addressed to Mark von Zastrow, Room N212, Genentech Hall, University of California at San Francisco Mission Bay Campus, 600 16th Street, San Francisco, CA 94158-2140. Email: mark.vonzastrow{at}ucsf.edu

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