title: Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Yingbei
authors.initials: Y
authors.lastname: Chen
authors.forename: Adrienne F
authors.initials: AF
authors.lastname: Jones
authors.forename: Richard H
authors.initials: RH
authors.lastname: Sanger
authors.forename: Leon P
authors.initials: LP
authors.lastname: Collis
authors.forename: Richard
authors.initials: R
authors.lastname: Flannery
authors.forename: Ewan C
authors.initials: EC
authors.lastname: McNay
authors.forename: Tingxi
authors.initials: T
authors.lastname: Yu
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Blaise
authors.initials: B
authors.lastname: Bossy
authors.forename: Ella
authors.initials: E
authors.lastname: Bossy-Wetzel
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.forename: Marc
authors.initials: M
authors.lastname: Pypaert
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: Peter J S
authors.initials: PJ
authors.lastname: Smith
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jonas
mesh_terms: 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*
chemical_list: D051020:bcl-X Protein; C519851:Dnm1l protein, rat; D034281:Dynamins