Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons.
Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.
Li
Hongmei
H
Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Chen
Yingbei
Y
Jones
Adrienne F
AF
Sanger
Richard H
RH
Collis
Leon P
LP
Flannery
Richard
R
McNay
Ewan C
EC
Yu
Tingxi
T
Schwarzenbacher
Robert
R
Bossy
Blaise
B
Bossy-Wetzel
Ella
E
Bennett
Michael V L
MV
Pypaert
Marc
M
Hickman
John A
JA
Smith
Peter J S
PJ
Hardwick
J Marie
JM
Jonas
Elizabeth A
EA
D000818:Animals; D002478:Cells, Cultured; D034281:Dynamins / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D051381:Rats; D013569:Synapses; D009435:Synaptic Transmission; D051020:bcl-X Protein / Q000502:physiology*
D051020:bcl-X Protein; C519851:Dnm1l protein, rat; D034281:Dynamins