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

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

Research output: Contribution to journalArticle

146 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2169-2174
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number6
DOIs
StatePublished - Feb 12 2008

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Dynamins
Synapses
Neurons
Proteins
GTP Phosphohydrolases
Mitochondria
Mitochondrial Dynamics
Synaptic Vesicles
Mitochondrial Proteins
Apoptosis

Keywords

  • ABT-737
  • Bcl-2
  • Cell death
  • Mitochondria
  • Synaptic transmission

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. / 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; Jonas, Elizabeth A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 6, 12.02.2008, p. 2169-2174.

Research output: Contribution to journalArticle

Li, H, Chen, Y, Jones, AF, Sanger, RH, Collis, LP, Flannery, R, McNay, EC, Yu, T, Schwarzenbacher, R, Bossy, B, Bossy-Wetzel, E, Bennett, MVL, Pypaert, M, Hickman, JA, Smith, PJS, Hardwick, JM & Jonas, EA 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, vol. 105, no. 6, pp. 2169-2174. https://doi.org/10.1073/pnas.0711647105
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 ; Jonas, Elizabeth A. / Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 6. pp. 2169-2174.
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AU - Sanger, Richard H.

AU - Collis, Leon P.

AU - Flannery, Richard

AU - McNay, Ewan C.

AU - Yu, Tingxi

AU - Schwarzenbacher, Robert

AU - Bossy, Blaise

AU - Bossy-Wetzel, Ella

AU - Bennett, Michael V. L.

AU - Pypaert, Marc

AU - Hickman, John A.

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N2 - 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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