title: Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate.
abstract: The energy required to fuse synaptic vesicles with the plasma membrane ('activation energy') is considered a major determinant in synaptic efficacy. From reaction rate theory, we predict that a class of modulations exists, which utilize linear modulation of the energy barrier for fusion to achieve supralinear effects on the fusion rate. To test this prediction experimentally, we developed a method to assess the number of releasable vesicles, rate constants for vesicle priming, unpriming, and fusion, and the activation energy for fusion by fitting a vesicle state model to synaptic responses induced by hypertonic solutions. We show that complexinI/II deficiency or phorbol ester stimulation indeed affects responses to hypertonic solution in a supralinear manner. An additive vs multiplicative relationship between activation energy and fusion rate provides a novel explanation for previously observed non-linear effects of genetic/pharmacological perturbations on synaptic transmission and a novel interpretation of the cooperative nature of Ca(2+)-dependent release.
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Sebastiaan
authors: S
authors: Schotten
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Marieke
authors: M
authors: Meijer
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Alexander Matthias
authors: AM
authors: Walter
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Vincent
authors: V
authors: Huson
authors: NeuroCure Cluster of Excellence, Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors: Lauren
authors: L
authors: Mamer
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Lawrence
authors: L
authors: Kalogreades
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Mirelle
authors: M
authors: ter Veer
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Marvin
authors: M
authors: Ruiter
authors: Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
authors: Nils
authors: N
authors: Brose
authors: NeuroCure Cluster of Excellence, Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors: Christian
authors: C
authors: Rosenmund
authors: Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Jakob Balslev
authors: JB
authors: Sørensen
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Matthijs
authors: M
authors: Verhage
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands.
authors: Lennart Niels
authors: LN
authors: Cornelisse
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008561:Membrane Fusion / Q000187:drug effects*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010703:Phorbol Esters / Q000494:pharmacology; D061251:Primary Cell Culture; D013395:Sucrose / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; C095992:complexin I; C095993:complexin II; D013395:Sucrose; D002118:Calcium
keywords: biophysics; fusion energy barrier; hypertonic stimulation; mathematical modelling; mouse; neuroscience; patch-clamp methodology; phorbol ester; structural biology; synaptic strength