FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels
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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 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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Recovery windows during repeated auditory cortex stimulation may also depend on intrinsic excitability and presynaptic BK channel deficits in Fmr1 KO mice (Deng et al., 2013), contributing to the habituation phenotype.
“Recovery windows during repeated stimulation in the auditory cortex may also depend on intrinsic excitability and deficits in presynaptic BK channels in Fmr1 KO mice (Deng et al., 2013) contributing to the habituation phenotype.”
From Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome (2016) · cites this paper as Deng et al., 2013
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- Authors
- Deng, P.-Y., Rotman, Z., Blundon, J. A., Cho, Y., Cui, J., Cavalli, V., Zakharenko, S. S., & Klyachko, V. A.
- Affiliations
- Washington University in St. Louis (US)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Klyachko, Vitaly A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 77
- Issue
- 4
- Pages
- 696-711
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3584349
- OpenAlex
- W2112137180
- Cited by
- 354
- References
- 39
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 21 · 2023: 22 · 2022: 37 · 2021: 18 · 2020: 34 · 2019: 36 · 2018: 26 · 2017: 20 · 2016: 33 · 2015: 25 · 2014: 30 · 2013: 17
- FWCI
- 23.20
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-04-10)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL070393)
- National Institute of Mental Health (R01MH095810, R01MH079079)
- National Institute of Neurological Disorders and Stroke (R01NS060706, R01NS060709, R01NS081972)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- FMRP, fragile X syndrome, BK channels, action potential duration, neurotransmitter release, presynaptic calcium influx, CA3 pyramidal cells, hippocampus, cortical pyramidal neurons, beta4 subunit, information theory
- MeSH terms
- Action Potentials, Animals, Calcium, Fragile X Syndrome, Hippocampus, Synaptic Transmission, Neurons, Presynaptic Terminals, Neurotransmitter Agents, Excitatory Postsynaptic Potentials, Large-Conductance Calcium-Activated Potassium Channels, Mice, Fragile X Messenger Ribonucleoprotein 1
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