The EC2 has a constant and a variable region, the latter contains several protein interaction sites (Berditchevski, 2001). All known tetraspanins contain the Cys-Cys-Gly sequence in the EC2, and >50% of tetraspanins buy Obeticholic Acid include a Pro-x-x-Cys-Cys sequence, that forms

disulfide bonds important for correct EC2 folding (Berditchevski, 2001). The N and C termini of individual tetraspanins are highly conserved across vertebrates, but differ markedly from one tetraspanin to the next; the C-terminal tail is especially divergent (Hemler, 2008). This suggests that, despite their short lengths, the N and C termini have specific functions, including linkage to cytoskeletal and signaling proteins. Tetraspanins regulate the signaling, trafficking and biosynthetic processing of associated proteins (Hemler, 2008), and may link the extracellular domain of α chain integrins with intracellular signaling molecules, including PI4K and PKC, both of which regulate cytoskeletal

architecture (Chavis and Westbrook, 2001, Hemler, 1998 and Yauch and Hemler, 2000). TM4SF2 transcripts are present in colon, muscle, heart, kidney, and spleen of mice, but are expressed most strongly in brain ( Hosokawa et al., 1999), primarily in neurons of frontal cortex, olfactory bulb, cerebellar cortex, caudoputamen, dentate gyrus, DAPT supplier and hippocampal CA3 ( Zemni why et al., 2000). Kainic acid treatment upregulates TM4SF2 mRNA, suggesting that TSPAN7 is involved in synaptic plasticity ( Boda et al., 2002). However, the function of TSPAN7 in the brain is unknown, and it is unclear how mutations affect neuronal development and function, and cause intellectual disability. To clarify TSPAN7′s

role in the brain, we examined its influence on the morphology and synaptic organization of developing hippocampal neurons. We focused on dendritic spines—main sites of excitatory synapses in the brain—because changes in spine morphology and density are associated with synaptic plasticity and learning (Kasai et al., 2010), and defects in spine morphology are associated with neurological disorders including intellectual disability (Humeau et al., 2009). We show that TSPAN7 promotes filopodia and dendritic spine formation in cultured hippocampal neurons, and is required for spine stability and normal synaptic transmission. We also identify PICK1 (protein interacting with C kinase 1) as a TSPAN7 partner. PICK1 is involved in the internalization and recycling of AMPA receptors (AMPARs) (Perez et al., 2001). Remarkably, TSPAN7 regulates the association of PICK1 with AMPARs, and controls AMPAR trafficking. These findings identify TSPAN7 as a key player in the morphological and functional maturation of glutamatergic synapses, and suggest how TSPAN7 mutations can give rise to intellectual disability.