Cytoplasmic FMR1 interacting protein 1 (Cyfip1), also named Shyc and Sra1, is a Rac1-interacting protein and a partner of the WAVE complex that regulates actin filament.
CYFIP1 is located on chromosome 15q11.2. Several studies have reported that patients with 15q11.2 microdeletions and microduplications between breakpoints 1 and 2, which encompass several genes including
CYFIP1, are diagnosed with neurodevelopmental disorders including ASD, ID, SCZ, attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) [
209,
210,
211,
212]. A paternally inherited rare variant of
CYFIP1 is found in an autistic patient with a de novo
SHANK2 deletion [
173]. Another paternally inherited rare variant of
CYFIP1 is found in a study on high functioning ASD patients [
213]. Additionally, SNPs in
CYFIP1 were reported to correlate with ASD in two studies [
214,
215]. A study on
CYFIP1 mRNA expression in human dorsolateral prefrontal cortex revealed higher expression of
CYFIP1 mRNA in ASD and classical autism patients, and identified several common variants of
CYFIP1 in these patients [
216]. A recent study also demonstrated significant increase in
CYFIP1 transcripts in the peripheral blood of ASD patients [
217]. All these clinical findings reveal that altered
CYFIP1 dosage may contribute to the pathology of ASD. Cyfip1 has been shown to interact with Rac1, Fragile X mental retardation 1 (FMRP), and eukaryotic translation initiation factor 4E (EIF4E) [
218,
219] (C). Cyfip1 is widely expressed in multiple tissues but not liver during development and is highly enriched in the hippocampus, cerebral cortex, cerebellum, olfactory bulb, and lateral septum in the adult brain [
220]. Levels of Cyfip1 are high in the cortex and cerebellum at the stages of postnatal development, peaked at P23 and slightly decreased afterwards [
221].
Four different strategies have been used for generation of
Cyfip1 KO mice. However, because Cyfip1 is very important for early embryonic development, none produce homozygous
Cyfip1 KO mice. Therefore,
Cyfip1 HET mice are used for studying behavioral and neural phenotypes in these studies. The first mouse model was generated by mutagenesis with a gene trap vector inserted into intron 1 of
Cyfip1. There are no
Cyfip1 KO embryos in breeding [
83].
Cyfip1 HET mice display normal learning and memory abilities in several memory tests, but show more rapid extinction in inhibitory avoidance test, a test for hippocampus-dependent memory [
83] (;
Supplementary Table S1). These results indicate that the accuracy of memory processing in HET mice is much poorer.
Cyfip1 HET mice show increased mGluR-dependent LTD and abnormal presynaptic function in hippocampal slices [
83,
222]. The second one is generated by deleting exons 4–6 of
Cyfip1. Inbreeded from
Cyfip1HET mice, fertilized
Cyfip1 KO oocytes are detectable in blastocyst stage [
223]. The KO embryos can survive until E8.5, but become lethal due to complete developmental failure [
223]. The
Cyfip1HET mice show absence of interest for social cues and deficits in motor learning [
84] (;
Supplementary Table S1). The third one is generated by deleting exon 5 of
Cyfip1, and the
Cyfip1 homozygous KO embryos die before E9.5 [
85]. Moreover, the difference between the maternal (m−/p+) and paternal (m+/p−) deficiency of
Cyfip1 was investigated. Interestingly,
Cyfip1 m−/p+ mice only display hypoactivity, whereas
Cyfip1 m+/p− mice display increased freezing in cued fear conditioning and abnormal transitions in zero-maze test [
85] (;
Supplementary Table S1). Both
Cyfip1 m-/p+ mice and
Cyfip1 m+/p- mice show reduced field EPSC and increased PPF in hippocampal CA1 region, and enhanced mGluR-dependent LTD is observed in
Cyfip1 m+/p- mice hippocampal CA1 neurons [
85]. The fourth one is generated by inserting a gene trap cassette between exon 12 and 13 of
Cyfip1.
Cyfip1+/- mice display impaired motor coordination, deficient sensory processing/novelty seeking behavior, reduced PPI, and decreased sensory motor gating [
86] (;
Supplementary Table S1), recapitulating some ASD and SCZ-like behavioral phenotypes.
Cyfip1+/- mice show reduced spontaneous neuronal activity and presynaptic function in cortical slices [
86]. Besides the whole-body mutant mice, one
Cyfip1 cKO mouse model (
Cyfip1NEX cKO mice) has been generated, in which exon 4–6 of
Cyfip1 was deleted in forebrain excitatory neurons by NEX-Cre. These mice are viable until adulthood with no obvious abnormalities [
224].
Cyfip1NEX cKO mice show increased mIPSC amplitude in hippocampal CA1 neurons and display similar deficits in dendrite morphology and spine maturation to those described in
Cyfip1 haploinsufficient models [
224]. There is also a
Cyfip1 mutant rat model generated by CRISPR/Cas9 technology, in which a 4 bp heterozygous deletion is introduced in exon 7 of
Cyfip1, causing premature stop of the protein [
87]. These
Cyfip1 haploinsufficient rats exhibit normal learning ability during all behavioral tests, but show deficits in behavioral flexibility [
87] (;
Supplementary Table S1). As increased transcript levels of
CYFIP1 is found in some ASD patients, two transgenic (Tg)
Cyfip1 mouse lines (Tg line 1 and Tg line 2) were generated by overexpressing human
CYFIP1. mRNA of human
CYFIP1 was increased in the cortex and hippocampus of both Tg lines; Cyfip1 protein is also increased in the two brain regions of Tg line 1 and the hippocampus of Tg line 2, but not in the cortex of Tg line 2 [
88]. Behaviorally, Tg line 2 mice display subtle defects of spatial learning memory and obvious increased fear response in contextual and cued fear conditioning test, whereas Tg line 1 mice show normal spatial learning memory and increased freezing only to the tone in the novel context during fear conditioning test [
88] (;
Supplementary Table S1). However, both Tg lines show no deficits in core ASD-related behaviors such as social and repetitive behaviors [
88] (;
Supplementary Table S1). Together,
Cyfip1 deficient mice or rats recapitulate core features of ASD, whereas
Cyfip1 Tg mice may not be appropriate ASD models.