These disorders are synaptopathies (Ehninger and Silva, 2009) in which dysgenesis of dendritic spines is a recurrent anatomical feature (Penzes et al., PD98059 in vivo 2011). Fragile X syndrome (FXS) is the most common form of inherited ID and a frequent monogenic cause of ASD (Belmonte and Bourgeron, 2006, Hatton et al., 2006, Jacquemont et al., 2007 and Turk, 2011). Patients

with FXS display dendritic spine defects (Irwin et al., 2001), neurodevelopmental delay, and autistic-like phenotype (Jacquemont et al., 2007). FXS is due to loss of function of the RNA-binding protein FMRP (Bagni et al., 2012 and Bassell and Warren, 2008), which regulates dendritic targeting of mRNAs (Dictenberg et al., 2008) and controls protein synthesis and mRNA decay in neuronal soma and at synapses (Bassell and Warren, 2008). High-throughput screenings

(Brown et al., 2001, Darnell et al., 2011, BMS-754807 supplier Klemmer et al., 2011, Liao et al., 2008 and Miyashiro et al., 2003) have revealed that a wide array of neuronal mRNAs is targeted by FMRP, suggesting that simultaneous dysregulation of many proteins contributes to FXS. A key functional partner of FMRP is the cytoplasmic FMRP-interacting protein 1, CYFIP1 (Napoli et al., 2008, Schenck et al., 2003 and Schenck et al., 2001) also known as “specific Rac1-activated” (SRA1) protein (Kobayashi et al., 1998). CYFIP1 is located within a hot spot for ASD (chr15q11.2), close to a region critical for two ASD-related syndromes: the Angelman and Prader-Willi syndromes. Microdeletions or microduplications of the region, including CYFIP1 and three other genes, cosegregate with cognitive disabilities and ASD ( Cooper et al.,

2011, Doornbos et al., 2009, Leblond et al., 2012, Nishimura et al., 2007, van der Zwaag et al., 2010 and von der Lippe et al., 2010). CYFIP1 messenger RNA (mRNA) is downregulated in a subgroup of FXS patients who have the Prader-Willi phenotype and show severe ASD and obsessive-compulsive Dichloromethane dehalogenase behavior ( Nowicki et al., 2007). In addition, CYFIP1 has recently been linked to schizophrenia (SCZ) ( Tam et al., 2010 and Zhao et al., 2012). Together with FMRP, CYFIP1 represses neuronal protein synthesis: FMRP tethers specific mRNAs to CYFIP1, which in turn sequesters the cap-binding protein eIF4E, thereby preventing initiation of translation (Napoli et al., 2008). Upon activation of the brain-derived neurotrophic factor (BDNF)/NT-3 growth factor receptor (TrkB) or group I metabotropic glutamate receptors (mGluRs), CYFIP1 is released from eIF4E and translation ensues (Napoli et al., 2008). Furthermore, CYFIP1 is part of the Wave Regulatory Complex (WRC), a heteropentamer containing also WAVE1/2/3, ABI1/2, NCKAP1 and HPSC300 (Takenawa and Suetsugu, 2007). The WRC regulates the actin-nucleating activity of the Arp2/3 complex and it can be activated through the small GTPase Rac1, kinases, and phospholipids (Chen et al., 2010, Eden et al., 2002 and Lebensohn and Kirschner, 2009).