Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Abstract

Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals.

Absence of TI-VAMP/Vamp7 Leads to Increased Anxiety in Mice

“…Immunocytochemistry was performed as previously described (Scheuber et al, 2006). Images of tissue section were acquired on a Leica SP5 confocal microscope by sequential scanning of the emission lines and manually adjusted to obtain the entire brain surface.…”

“…TI-VAMP was proposed to mediate the release of neurotransmitters at a subset of synapses (Scheuber et al, 2006). This led us to characterize behavioral alterations in TI-VAMP KO male mice as possible consequences of presynaptic defects.…”

“…TI-VAMP is resistant to clostridial neurotoxins unlike VAMPs 1/2/3, defining clostridial neurotoxin-resistant pathways. TI-VAMP contains an N-terminal extension of ϳ100 aa called Longin domain which has two functions: it binds to the ␦ subunit of the molecular coat AP-3 to target TI-VAMP to synaptic vesicles (Scheuber et al, 2006), and it inhibits the formation of SNARE complexes . TI-VAMP interacts with plasma membrane and endosomal t-SNAREs, and is necessary for lysosomal and granule secretion in several cell types (for review, see Chaineau et al, 2009).…”

Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

“…In these animals, ZnT3 levels are drastically reduced, indicating that AP3 is responsible for the recruitment of the zinc transporter into vesicles that are generated via bulk endocytosis (Kantheti et al, 1998;Salazar et al, 2004a). mocha mice also lack the tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP or VAMP7) and show the loss of asynchronous evoked release at hippocampal MFs (Scheuber et al, 2006). These studies demonstrate that AP3 is responsible for the recruitment of ZnT3 and VAMP7 into a subset of vesicles and therefore very likely that ZnT3 and VAMP7 are expressed on the same population of synaptic vesicles.…”

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

“…Lack of functional AP-3 results in mislocalization of VAMP7 to early endosomes and hence impaired secretion of lysosome-related organelles (Martinez-Arca et al, 2003;ProuxGillardeaux et al, 2007). mocha mice are characterized by a coat color defect, prolonged bleeding times, and in addition suffer from a series of neurological deficits including seizures (Kantheti et al, 1998;Scheuber et al, 2006;Danglot and Galli, 2007), which may primarily depend on missorting of VAMP7.…”