Cyfip1 Regulates Presynaptic Activity during Development
Open accessAbstract
Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous for Cyfip1 have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors. SIGNIFICANCE STATEMENT Several developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins. Cyfip1 is one such protein, but the role it plays in brain development is poorly understood. We asked whether decreased Cyfip1 levels altered the function of developing synapses. The data show that synapses with reduced Cyfip1 are larger and release neurotransmitter more rapidly. These effects are due to Cyfip1's role in actin polymerization and are reversed by expression of a Cyfip1 mutant protein retaining actin regulatory function or by inhibiting Rac1. Thus, Cyfip1 has a more prominent early role regulating presynaptic activity during a stage of development when activity helps to define neural pathways.
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CYFIP1 plays a role in determining the presynaptic terminal size and vesicle release probability during development.
“CYFIP1 plays a role in determining the presynaptic terminal size and vesicle release probability during development73.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [73]
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“Cy fi p1 heterozygous mice ( Cy fi p1 +/- ) have reduced functional connectivity and altered presynaptic function 28,31 .”
- Authors
- Hsiao, K., Harony-Nicolas, H., Buxbaum, J. D., Bozdagi-Gunal, O., & Benson, D. L.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-02-03
- Volume
- 36
- Issue
- 5
- Pages
- 1564-1576
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4737770
- OpenAlex
- W2312587001
- Cited by
- 64
- References
- 10
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 2
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beatrice and Samuel A. Seaver Foundation
- National Institute of Mental Health (R01MH103455)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CYFIP1, presynaptic function, synaptic development, hippocampus, WAVE regulatory complex, Rac1, actin polymerization, F-actin, paired-pulse facilitation, miniature EPSCs, mRNA translation, copy number variation, autism spectrum disorder, schizophrenia
- MeSH terms
- Animals, Cells, Cultured, Hippocampus, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Rats, Sprague-Dawley, Presynaptic Terminals, Adaptor Proteins, Signal Transducing, Mice, Rats
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