Reelin Mobilizes a VAMP7-Dependent Synaptic Vesicle Pool and Selectively Augments Spontaneous Neurotransmission

• Published in: Neuron (Cambridge, Mass.) Mass.), 2013-11, Vol.80 (4), p.934-946
• Main Authors: Bal, Manjot, Leitz, Jeremy, Reese, Austin L., Ramirez, Denise M.O., Durakoglugil, Murat, Herz, Joachim, Monteggia, Lisa M., Kavalali, Ege T.
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - metabolism; Brain research; Calcium Signaling - physiology; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - physiology; Cells, Cultured; Electrophysiological Phenomena; Excitatory Postsynaptic Potentials - physiology; Experiments; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - physiology; Female; Kinases; Lentivirus - genetics; Low density lipoprotein receptors; Male; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurons; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases - metabolism; Proteins; R-SNARE Proteins - genetics; R-SNARE Proteins - physiology; Rats; Rats, Sprague-Dawley; Serine Endopeptidases - genetics; Serine Endopeptidases - physiology; SNARE Proteins - metabolism; Synaptic Transmission - physiology; Synaptic Vesicles - physiology; Synaptosomal-Associated Protein 25 - genetics; Synaptosomal-Associated Protein 25 - physiology; Tetrodotoxin - pharmacology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.08.024

Reelin is a glycoprotein that is critical for proper layering of neocortex during development as well as dynamic regulation of glutamatergic postsynaptic signaling in mature synapses. Here, we show that Reelin also acts presynaptically, resulting in robust rapid enhancement of spontaneous neurotransmitter release without affecting properties of evoked neurotransmission. This effect of Reelin requires a modest but significant increase in presynaptic Ca2+ initiated via ApoER2 signaling. The specificity of Reelin action on spontaneous neurotransmitter release is encoded at the level of vesicular SNARE machinery as it requires VAMP7 and SNAP-25 but not synaptobrevin2, VAMP4, or vti1a. These results uncover a presynaptic regulatory pathway that utilizes the heterogeneity of synaptic vesicle-associated SNAREs and selectively augments action potential-independent neurotransmission. •Reelin selectively augments spontaneous synaptic transmission•The effect of Reelin requires ApoER2 and VLDLR activation, PI3K activity, and Ca2+•Reelin selectively acts on VAMP7 expressing synaptic vesicles within a synapse•VAMP7 knockdown abolishes the effect of Reelin Bal et al. find that the secreted glycoprotein Reelin selectively augments spontaneous neurotransmitter release by mobilizing vesicles enriched with the SNARE protein VAMP7, uncovering a presynaptic pathway that utilizes the heterogeneity of synaptic vesicle SNAREs to potentiate spontaneous neurotransmission.