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Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons

Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons
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.
0027-8424
2169-2174
Li, Hongmei
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Chen, Yingbei
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Jones, Adrienne F.
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Sanger, Richard H.
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Collis, Leon P.
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Flannery, Richard
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McNay, Ewan C.
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Yu, Tingxi
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Schwarzenbacher, Robert
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Bossy, Blaise
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Bossy-Wetzel, Ella
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Bennett, Michael V.L.
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Pypaert, Marc
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Hickman, John A.
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Smith, Peter J.S.
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Hardwick, J. Marie
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Jonas, Elizabeth A.
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Li, Hongmei
dc6391b3-b510-4e46-8b24-dcdca3e73190
Chen, Yingbei
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Jones, Adrienne F.
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Sanger, Richard H.
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Collis, Leon P.
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Flannery, Richard
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McNay, Ewan C.
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Yu, Tingxi
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Schwarzenbacher, Robert
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Bossy, Blaise
123a1925-3e64-4c78-af49-62607d9ea187
Bossy-Wetzel, Ella
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Bennett, Michael V.L.
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Pypaert, Marc
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Hickman, John A.
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Smith, Peter J.S.
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Hardwick, J. Marie
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Jonas, Elizabeth A.
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Li, Hongmei, Chen, Yingbei, Jones, Adrienne F., Sanger, Richard H., Collis, Leon P., Flannery, Richard, McNay, Ewan C., Yu, Tingxi, Schwarzenbacher, Robert, Bossy, Blaise, Bossy-Wetzel, Ella, Bennett, Michael V.L., Pypaert, Marc, Hickman, John A., Smith, Peter J.S., Hardwick, J. Marie and Jonas, Elizabeth A. (2008) Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America, 105 (6), 2169-2174. (doi:10.1073/pnas.0711647105). (PMID:18250306)

Record type: Article

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.

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Published date: 12 February 2008
Additional Information: Bcl-2, synaptic transmission, mitochondria, cell death, ABT-737
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 188771
URI: http://eprints.soton.ac.uk/id/eprint/188771
ISSN: 0027-8424
PURE UUID: 12912539-27a6-416c-962a-aa81c89afdea
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 27 May 2011 15:36
Last modified: 27 Oct 2023 01:51

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Contributors

Author: Hongmei Li
Author: Yingbei Chen
Author: Adrienne F. Jones
Author: Richard H. Sanger
Author: Leon P. Collis
Author: Richard Flannery
Author: Ewan C. McNay
Author: Tingxi Yu
Author: Robert Schwarzenbacher
Author: Blaise Bossy
Author: Ella Bossy-Wetzel
Author: Michael V.L. Bennett
Author: Marc Pypaert
Author: John A. Hickman
Author: J. Marie Hardwick
Author: Elizabeth A. Jonas

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