The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles - PubMed (original) (raw)

Review

The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles

Emma L Clayton et al. J Neurochem. 2009 Nov.

Abstract

Central nerve terminals release neurotransmitter in response to a wide variety of stimuli. Because maintenance of neurotransmitter release is dependent on the continual supply of synaptic vesicles (SVs), nerve terminals possess an array of endocytosis modes to retrieve and recycle SV membrane and proteins. During mild stimulation conditions, single SV retrieval modes such as clathrin-mediated endocytosis predominate. However, during increased neuronal activity, additional SV retrieval capacity is required, which is provided by activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mechanism during elevated neuronal activity. It is a high capacity SV retrieval mode that is immediately triggered during such stimulation conditions. This review will summarize the current knowledge regarding the molecular mechanism of ADBE, including molecules required for its triggering and subsequent steps, including SV budding from bulk endosomes. The molecular relationship between ADBE and the SV reserve pool will also be discussed. It is becoming clear that an understanding of the molecular physiology of ADBE will be of critical importance in attempts to modulate both normal and abnormal synaptic function during intense neuronal activity.

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Figures

Figure 1

Figure 1. Activity-dependent selection of different SV retrieval modes in central nerve terminals

HRP was applied to primary neuronal cultures during trains of either 200 (A, 10 Hz), 400 (C, 40 Hz) or 800 (E, 80 Hz) action potentials and then immediately fixed. Alternatively HRP was applied to cultures for 5 min immediately after trains of either 200 (B, 10 Hz), 400 (D, 40 Hz) or 800 (F, 80 Hz) action potentials and then fixed. Representative electron micrographs are displayed (A-F). The number of HRP-labelled SVs (grey bars) or HRP-labelled endosomes (black bars) are diplayed that were generated either during (G) or after (H) stimulation is displayed. Note that with increasing stimulation intensity the number of HRP-labelled SVs does not increase, whereas at a certain threshold the number of HRP-labelled endosomes increases greatly. Also after stimulation note that the dominant SV retrieval mode is CME and not ADBE. From Clayton et al (2008) reproduced with permission, by the Society for Neuroscience.

Figure 2

Figure 2. Selection of different SV retrieval modes by activity-dependent dynamin I dephosphorylation

During mild neuronal activity increases in intracellular free calcium are restricted to the active zone. This results in only a few SVs fusing with the plasma membrane and no activation of cytosolic calcineurin. CME can still proceed however, since phospho-dynamin I binds to amphiphysin irrespective of its phosphorylation status. Intense neuronal activity leads to increases in intracellular free calcium outside the active zone, due to the build up of residual calcium in the nerve terminal. This triggers both increased SV fusion and activation of cytosolic calcineurin. Active calcineurin then dephosphorylates dynamin I allowing an interaction with syndapin in addition to its phospho-independent interaction with amphiphysin. Thus two SV retrieval modes are now triggered, CME (which is dependent on the dynamin - amphiphysin interaction) and ADBE (which is dependent on the dynamin - syndapin interaction). Therefore both SV retrieval modes are dynamin-dependent, however only ADBE is dependent on the dephosphorylation of dynamin I.

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