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Bassani, Silvia (2)
Passafaro, Maria (2)
Cingolani, Lorenzo A. (1)
Folci, Alessandra (1)
Gianfelice, Antonella (1)
Goda, Yukiko (1)
Sala, Carlo (1)
Valnegri, Pamela (1)
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Tetraspanins regulate the signaling, trafficking and biosynthetic processing of associated proteins, and may link the extracellular domain of α-chain integrins with intracellular signaling molecules, including PI4K and PKC, both of which regulate cytoskeletal architecture. We showed that TSPAN7, a member of tetraspannin-family, promotes filopodia and dendritic spine formation in cultured hippocampal neurons, and is required for spine stability and normal synaptic transmission. TSPAN7 directly interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), and associates with AMPAR subunit GluA2 and β1-integrin. TSPAN7 regulates PICK1 and GluA2/3 association, and AMPA receptor trafficking. These findings identify TSPAN7 as a key player in the morphological and functional maturation of glutamatergic synapses.
intellectual disability; AMPAR trafficking; synapse function/plasticity; tetrasapanins; TSPAN7; integrins; PICK1
The X-Linked Intellectual Disability Protein TSPAN7 Regulates Excitatory Synapse Development and AMPAR Trafficking
Cingolani, Lorenzo A.
Mutations in TSPAN7—a member of the tetraspanin protein superfamily—are implicated in some forms of X-linked intellectual disability. Here we show that TSPAN7 overexpression promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats, whereas TSPAN7 silencing reduces head size and stability of spines and AMPA receptor currents. Via its C terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking. These findings indicate that, in hippocampal neurons, TSPAN7 regulates AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability.
► TSPAN7 is required for spine maturation in hippocampal neurons ► TSPAN7 knockdown impairs AMPAR currents ► TSPAN7 binds PICK1 and through this interaction regulates AMPAR trafficking
Mutations in TSPAN7 protein cause human intellectual disability. Bassani et al. now find that TSPAN7 regulates trafficking of essential receptor proteins to neuron surfaces and that absence impairs neuronal maturation in young animals, potentially underlying this intellectual disability.
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