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
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Our results demonstrate that FMRP regulates neurotransmitter release in CA3 pyramidal neurons via modulation of AP duration. Acute rescue experiments indicate that this function of FMRP is translation independent and has a cell-autonomous presynaptic origin. The axonal/presynaptic locus of FMRP actions on AP waveform is supported by recordings of compound APs in the vicinity of presynaptic terminals and by direct measurements of presynaptic calcium influx. In WT neurons, FMRP acts to limit AP broadening during repetitive activity by modulating the activity of BK channels, specifically their calcium sensitivity. This function of FMRP is mediated by an interaction between FMRP and the BK channel’s regulatory β4 subunit. Loss of FMRP causes reduced BK channel activity and excessive AP broadening, leading in turn to elevated presynaptic calcium influx, increased synaptic transmission, and STP during repetitive activity. Information analysis suggests that the defects in neurotransmitter release and STP associated with FMRP loss cause marked abnormalities in synaptic information transmission. Taken together, these results reveal a major translation-independent presynaptic role of FMRP in regulating neurotransmitter release and synaptic information transmission. Our observation that FMRP modulates AP duration both in the hippocampal and cortical pyramidal neurons suggests that FMRP regulation of presynaptic function may be a widespread phenomenon that could play a role in the pathophysiology of FXS.
ASJC Scopus subject areas
- General Neuroscience