Title

Bcl-X-L induces Drp1-dependent synapse formation in cultured hippocampal neurons

Authors

Authors

H. Li; Y. Chen; A. F. Jones; R. H. Sanger; L. P. Collis; R. Flannery; E. C. McNay; T. X. Yu; R. Schwarzenbacher; B. Bossy; E. Bossy-Wetzel; M. V. L. Bennett; M. Pypaert; J. A. Hickman; P. J. S. Smith; J. M. Hardwick;E. A. Jonas

Comments

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Abbreviated Journal Title

Proc. Natl. Acad. Sci. U. S. A.

Keywords

Bcl-2; synaptic transmission; mitochondria; cell death; ABT-737; MITOCHONDRIAL FISSION; CELL-DEATH; EMBRYONIC NEURONS; AXONAL-TRANSPORT; APOPTOSIS; RELEASE; DYNAMICS; FUSION; BAX; TRANSMISSION; Multidisciplinary Sciences

Abstract

Maturation of neuronal synapses is thought to involve mitochondria. Bcl-X-L protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-X-L is abundant. Here, we report that overexpression of Bcl-X-L postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-X-L, 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-X-L 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-X-L appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-X-L coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-X-L protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-X-L positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

105

Issue/Number

6

Publication Date

1-1-2008

Document Type

Article

Language

English

First Page

2169

Last Page

2174

WOS Identifier

WOS:000253261900071

ISSN

0027-8424

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