The initial contacts between axons and dendrites are mediated by specific adhesion-related proteins, such as neurexin and neuroligin (e.g., NRXN1 and NLGN3, genes perturbed by rare de novo CNVs associated with ASD are underlined here and below) ( Südhof, 2008). On the postsynaptic side of an excitatory synapse, the initial axon-dendrite contacts ultimately develop into a complex and dense structure, the postsynaptic density (PSD), dominated by several types of glutamate receptors (such as AMPA and NMDA), various scaffolding proteins (DLG4/PSD95, DLG2, SHANK2/3,

SynGAP1, DLGAP2) and trafficking/signaling proteins (CTNND2). In total, the PSD contains many hundreds of distinct Alisertib clinical trial proteins ( Bayés et al., 2011 and Sheng and Hoogenraad, 2007). Information for activity-dependent regulation of spine morphology is passed through an intermediate level of signaling protein, such as Rho family ( Linseman and Loucks, 2008) of small GTPases (RhoA/B, Cdc42, Rac1) to downstream targets (LIMK1 and PAK1/2/3) connected to proteins modifying morphology of the actin network (cofilin and Arp2/3) ( Blanchoin et al., 2000). The activity of the GTPases is regulated pre-

or postsynaptically by many guanine exchange factors (GEFs), GDP dissociation inhibitors (GDIs, such as GDI1) and GTP-activating PF-01367338 cell line proteins (GAPs). Many other proteins shown in Figure 3, such as FLNA, CTNNA3, DOCK8, SPTAN1, CYFIP1, either bind directly to the actin network or mediate interaction of actin filaments with other proteins. The WNT signaling pathway plays a crucial role in diverse processes associated with formation of neural circuits (Salinas and Zou, 2008). This pathway is also known to be directly involved in the regulation of dendrite morphogenesis (Rosso et al., 2005 and Salinas et al., 1994). WNT signaling Megestrol Acetate is accomplished through the canonical branch (DVL, AXIN1, beta-catenin) and the noncanonical branch (DVL1/2/3, Rac1, and JNK); both of these pathway branches converge on regulation of actin network morphogenesis.

Similar to WNT, the reelin signaling also plays a prominent role in the context of autism phenotype and specifically dendritic spine morphogenesis ( Fatemi et al., 2005 and Niu et al., 2008). Signaling by secreted extracellular RELN protein acts though VLDR and Apoer2 receptors and the PI3K/Akt pathway ( Jossin and Goffinet, 2007) regulating the mammalian target of rapamycin (mTOR) pathway ( Kumar et al., 2005 and Shaw and Cantley, 2006). Another important pathway converging on mTOR involves MAPK3/ERK, which can be activated by Ras and NF1. mTOR integrates various inputs from upstream growth-related pathways, and is also known to regulate dendrite morphogenesis ( Tavazoie et al., 2005).