Journal
NEURON
Volume 77, Issue 4, Pages 696-711Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2012.12.018
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Funding
- NINDS [R01 NS081972, RO1 NS060709, R01 NS060706]
- FRAXA Foundation
- Edward Mallinckrodt Jr. Foundation
- McDonnell Center for Systems Neuroscience
- NIMH [R01 MH079079, R01 MH095810]
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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 beta 4 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.
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