The X-linked intellectual disability protein TSPAN7 regulates excitatory synapse development and AMPAR trafficking

Neuron. 2012 Mar 22;73(6):1143-58. doi: 10.1016/j.neuron.2012.01.021. Epub 2012 Mar 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biophysics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dendritic Spines / drug effects
  • Dendritic Spines / genetics
  • Dendritic Spines / physiology*
  • Disks Large Homolog 4 Protein
  • Electric Stimulation
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Humans
  • Hydrazones / pharmacology
  • Immunoprecipitation
  • In Vitro Techniques
  • Integrin beta1 / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics
  • Membrane Proteins / metabolism
  • Microscopy, Confocal
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / physiology*
  • Nuclear Proteins / metabolism
  • Patch-Clamp Techniques
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Pseudopodia / drug effects
  • Pseudopodia / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Receptors, AMPA / metabolism*
  • Synapses / genetics
  • Synapses / physiology*
  • Tetraspanins / genetics
  • Tetraspanins / metabolism*
  • Time Factors
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • Carrier Proteins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Hydrazones
  • Integrin beta1
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PICk1 protein, human
  • RNA, Small Interfering
  • Receptors, AMPA
  • TSPAN7 protein, human
  • Tetraspanins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins