Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 6, Pages 2169-2174Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0711647105
Keywords
Bcl-2; synaptic transmission; mitochondria; cell death; ABT-737
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Funding
- NCRR NIH HHS [P41 RR001395] Funding Source: Medline
- NEI NIH HHS [R01 EY016164] Funding Source: Medline
- NINDS NIH HHS [NS037402, R01 NS037402, R37 NS045876, R01 NS045876, NS045876] Funding Source: Medline
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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.
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