FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels

Pan Yue Deng, Ziv Rotman, Jay A. Blundon, Yongcheol Cho, Jianmin Cui, Valeria Cavalli, Stanislav S. Zakharenko, Vitaly A. Klyachko

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel@s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology

Original languageEnglish
Pages (from-to)696-711
Number of pages16
JournalNeuron
Volume77
Issue number4
DOIs
Publication statusPublished - 2013 Feb 20
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Deng, P. Y., Rotman, Z., Blundon, J. A., Cho, Y., Cui, J., Cavalli, V., Zakharenko, S. S., & Klyachko, V. A. (2013). FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels. Neuron, 77(4), 696-711. https://doi.org/10.1016/j.neuron.2012.12.018