Mechanisms of Synaptic Vesicle Recycling
Neuronal signaling involves the release of neurotransmitter at the synapse,
a specialized site of interneuronal contact. Nonpeptide neurotransmitters
are stored in synaptic vesicles (SVs), specialized secretory organelles of
presynaptic nerve terminals. SVs undergo calcium-regulated exocytosis upon
depolarization of the nerve terminal and subsequent entry of calcium. In order
to sustain neurotransmitter release under conditions of stimulation at high frequency
and the corresponding massive insertion of vesicular proteins and lipids into the
plasma membrane, SVs are recycled by clathrin-mediated endocytosis at the outer
margin of the active zone (Fig. 1).
Figure 1: A reticulospinal synapse in the lamprey spinal cord stimulated at 5 Hz. Boxed areas show clathrin-mediated intermediates budding from the pre-synaptic endocytic zone (D), from the post-synaptic membrane (E), and from an endocytic compartment of the post-synaptic dendrite, d (F). Courtesy of Dr. Oleg Shupliakov,
Karolinska Institute; see Shupliakov & Haucke, 2006
Whether another, fast, clathrin-independent mode of kiss-and-run exo-endocytosis co-exists at central synapses remains under debate [see i.e. T. Galli, V. Haucke, Cycling of synaptic vesicles:
How far? How fast! Sci. STKE 2004, re19 (2004); Fig. 2].
Figure 2: Schematic depicting the various proposed modes of synaptic vesicle (SV) recycling. A fast 'kiss-and-run' mechanism, where the vesicle connects only briefly to the plasma membrane without full collapse ("kiss & run"), a slow pathway via large infoldings and endosomes ("bulk endocytosis"), and recovery of vesicle membrane by clathrin-coated pits
(clathrin-mediated endocytosis, "CME"). Taken from Haucke & Klingauf, 2006.
A strict coupling between the exo- and endocytotic steps is essential for proper signaling at the synapse, because imbalances between the two can lead to expansion or shrinkage of the plasma membrane and can alter the size of the pool of SVs. We are investigating key aspects of this process by combining mouse genetics, protein biochemical studies, and cell bioogical methods. In collaboration with the labs of Drs. J. Klingauf (Max-Planck-Institute for Biophysical Chemistry, Goettingen) and D. Schmitz (Neuroscience Research Center, Charite, Berlin) we are also analyzing these processes by optical imaging and electrophysiology.
A detailed description of SV recycling mechanisms is given in: T. Galli, V. Haucke, Cycling of synaptic vesicles: How far? How fast! Sci. STKE 2004, re19 (2004
The following small animation provides an overview of the SV cycle.
Animation 1. Slow track for synaptic vesicle retrieval by clathrin-mediated endocytosis.
The animation illustrates the recruitment, calcium-triggered fusion,
and clathrin-mediated endocytosis of synaptic vesicles.
Use the buttons to proceed through the animation, to step back, or to restart.
Last update: Nov, 2005 by Claus Rodemer
