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1.  The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition 
Nature Communications  2015;6:6504.
RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca2+-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders.
Mutations in the RAB39B gene, which encodes a protein involved in vesicular trafficking, are associated with intellectual disability, but the impact of RAB39B loss of function on synaptic activity is not known. Here the authors show that RAB39B interacts with PICK1, and that this interaction is critical for the translocation of AMPA receptor subunits into the Golgi.
doi:10.1038/ncomms7504
PMCID: PMC4383008  PMID: 25784538
2.  TSPAN7 
Bioarchitecture  2012;2(3):95-97.
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.
doi:10.4161/bioa.20829
PMCID: PMC3414387  PMID: 22880149
intellectual disability; AMPAR trafficking; synapse function/plasticity; tetrasapanins; TSPAN7; integrins; PICK1
3.  The X-Linked Intellectual Disability Protein TSPAN7 Regulates Excitatory Synapse Development and AMPAR Trafficking 
Neuron  2012;73(6):1143-1158.
Summary
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.
Highlights
► 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.
doi:10.1016/j.neuron.2012.01.021
PMCID: PMC3314997  PMID: 22445342

Results 1-3 (3)