SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

Lucas Matt, Lyndsey M. Kirk, George Chenaux, David J. Speca, Kyle R. Puhger, Michael C. Pride, Mohammad Qneibi, Tomer Haham, Kristopher E. Plambeck, Yael Stern-Bach, Jill L Silverman, Jacqueline Crawley, Johannes W Hell, Elva D Diaz

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Altering AMPA receptor (AMPAR) content at synapses is a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 (synapse differentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapse strength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistry and electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation (LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapse development and function underlying higher-order cognitive plasticity. Matt et al. show that mice lacking the AMPAR-associated protein SynDIG4/Prrt1 display deficits in synaptic plasticity and cognition. SynDIG4 modifies AMPAR biophysical properties in heterologous cells, but synaptic AMPAR kinetics are unchanged, suggesting that SynDIG4 establishes a pool of extrasynaptic AMPARs necessary for higher-order cognitive plasticity.

Original languageEnglish (US)
Pages (from-to)2455-2468
Number of pages14
JournalCell Reports
Volume22
Issue number9
DOIs
StatePublished - Feb 27 2018

Keywords

  • auxiliary factor
  • excitatory synapse
  • extrasynaptic AMPARs
  • hippocampus
  • LTP
  • NG5
  • Prrt1
  • SynDIG family
  • SynDIG4

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Matt, L., Kirk, L. M., Chenaux, G., Speca, D. J., Puhger, K. R., Pride, M. C., Qneibi, M., Haham, T., Plambeck, K. E., Stern-Bach, Y., Silverman, J. L., Crawley, J., Hell, J. W., & Diaz, E. D. (2018). SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function. Cell Reports, 22(9), 2455-2468. https://doi.org/10.1016/j.celrep.2018.02.026