RGD Reference Report - Cyfip1 Regulates Presynaptic Activity during Development. - Rat Genome Database

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Cyfip1 Regulates Presynaptic Activity during Development.

Authors: Hsiao, K  Harony-Nicolas, H  Buxbaum, JD  Bozdagi-Gunal, O  Benson, DL 
Citation: Hsiao K, etal., J Neurosci. 2016 Feb 3;36(5):1564-76. doi: 10.1523/JNEUROSCI.0511-15.2016.
RGD ID: 11342679
Pubmed: (View Article at PubMed) PMID:26843638
DOI: Full-text: DOI:10.1523/JNEUROSCI.0511-15.2016

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.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component

Objects Annotated

Genes (Rattus norvegicus)
Cyfip1  (cytoplasmic FMR1 interacting protein 1)


Additional Information