TY - JOUR
T1 - Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons
AU - Li, Hongmei
AU - Chen, Yingbei
AU - Jones, Adrienne F.
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.
AU - Smith, Peter J.S.
AU - Hardwick, J. Marie
AU - Jonas, Elizabeth A.
PY - 2008/2/12
Y1 - 2008/2/12
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.
AB - 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.
KW - ABT-737
KW - Bcl-2
KW - Cell death
KW - Mitochondria
KW - Synaptic transmission
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UR - http://www.scopus.com/inward/citedby.url?scp=41149111891&partnerID=8YFLogxK
U2 - 10.1073/pnas.0711647105
DO - 10.1073/pnas.0711647105
M3 - Article
C2 - 18250306
AN - SCOPUS:41149111891
SN - 0027-8424
VL - 105
SP - 2169
EP - 2174
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -