FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Katherine Bonnycastle, Peter C Kind, Michael A Cousin

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from male Fmr1 knock-out (KO) rats display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 KO neurons to sustain SV recycling during trains of high-frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in KO neurons, however this dysfunction was corrected by BK channel agonists. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of ADBE, suggesting intervention via this endocytosis mode may correct the hyperexcitability observed in FXS.

Original languageEnglish
Pages (from-to)1618-1628
JournalJournal of Neuroscience
Issue number8
Early online date7 Jan 2022
Publication statusPublished - 23 Feb 2022

Keywords / Materials (for Non-textual outputs)

  • endocytosis
  • FMRP
  • fragile X syndrome
  • presynapse
  • vesicle


Dive into the research topics of 'FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis'. Together they form a unique fingerprint.

Cite this