Septins regulate developmental switching from microdomain to nanodomain coupling of Ca(2+) influx to neurotransmitter release at a central synapse.
Neurotransmitter release depends critically on close spatial coupling of Ca(2+) entry to synaptic vesicles at the nerve terminal; however, the molecular substrates determining their physical proximity are unknown. Using the calyx of Held synapse, where "microdomain" coupling predominates at immature stages and developmentally switches to "nanodomain" coupling, we demonstrate that deletion of the filamentous protein Septin 5 imparts immature synapses with striking morphological and functional features reminiscent of mature synapses. This includes synaptic vesicles tightly localized to active zones, resistance to the slow Ca(2+) buffer EGTA and a reduced number of Ca(2+) channels required to trigger single fusion events. Disrupting Septin 5 organization acutely transforms microdomain to nanodomain coupling and potentiates quantal output in immature wild-type terminals. These observations suggest that Septin 5 is a core molecular substrate that differentiates distinct release modalities at the central synapse.
Yang
Yi-Mei
YM
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
Fedchyshyn
Michael J
MJ
Grande
Giovanbattista
G
Aitoubah
Jamila
J
Tsang
Christopher W
CW
Xie
Hong
H
Ackerley
Cameron A
CA
Trimble
William S
WS
Wang
Lu-Yang
LY
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000254:growth & development; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000254:growth & development / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D020555:GTP-Binding Protein Regulators / Q000235:genetics; D066298:In Vitro Techniques; D021962:Membrane Microdomains / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D051140:Selenoproteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
D000906:Antibodies; C484094:CDC42EP5 protein, human; D002614:Chelating Agents; D020555:GTP-Binding Protein Regulators; D018377:Neurotransmitter Agents; C495239:Selenof protein, mouse; D051140:Selenoproteins; D050598:Vesicular Glutamate Transport Protein 1; D002118:Calcium