Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.
Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) has an important function in cell regulation both as a precursor of second messenger molecules and by means of its direct interactions with cytosolic and membrane proteins. Biochemical studies have suggested a role for PtdIns(4,5)P2 in clathrin coat dynamics, and defects in its dephosphorylation at the synapse produce an accumulation of coated endocytic intermediates. However, the involvement of PtdIns(4,5)P2 in synaptic vesicle exocytosis remains unclear. Here, we show that decreased levels of PtdIns(4,5)P2 in the brain and an impairment of its depolarization-dependent synthesis in nerve terminals lead to early postnatal lethality and synaptic defects in mice. These include decreased frequency of miniature currents, enhanced synaptic depression, a smaller readily releasable pool of vesicles, delayed endocytosis and slower recycling kinetics. Our results demonstrate a critical role for PtdIns(4,5)P2 synthesis in the regulation of multiple steps of the synaptic vesicle cycle.
Di Paolo
Gilbert
G
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Moskowitz
Howard S
HS
Gipson
Keith
K
Wenk
Markus R
MR
Voronov
Sergey
S
Obayashi
Masanori
M
Flavell
Richard
R
Fitzsimonds
Reiko M
RM
Ryan
Timothy A
TA
De Camilli
Pietro
P
D000200:Action Potentials; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004553:Electric Conductivity; D004705:Endocytosis; D005089:Exocytosis; D017353:Gene Deletion; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*
D002966:Clathrin; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase