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${\rm Bcl}\text{-}{\rm x}_{{\rm L}}$ 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 and Elizabeth A. Jonas
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 6 (Feb. 12, 2008), pp. 2169-2174
Stable URL: http://www.jstor.org/stable/25451432
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
${\rm Bcl}\text{-}{\rm x}_{{\rm L}}$
          Induces Drp1-Dependent Synapse Formation in Cultured Hippocampal Neurons
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Abstract

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

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