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 N. Crawley, Johannes W. Hell*, Elva Díaz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 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 languageAmerican English
Pages (from-to)2246-2253
Number of pages8
JournalCell Reports
Volume22
Issue number9
DOIs
StatePublished - 27 Feb 2018

Bibliographical note

Funding Information:
Funding was provided by the American Heart Association ( 11POST7020009 to L.M.), Brain & Behavior Research Foundation NARSAD Young Investigator (grant 20748 to L.M.), United States-Israel Binational Science Foundation (BSF; grant 2012781 to Y.S.-B.) and the United States National Science Foundation (NSF; grant 1322302 to E.D.), NIH ( R01 MH097887 to J.W.H., R01 NS078792 to J.W.H., U54 HD079125 MCP to J.L.S. and J.N.C.) and NIH New Director’s Innovator Award Program ( DP2 OD006479-01 to E.D.), UC Davis Academic Senate Research Program Pilot Grant (to E.D.), and Whitehall Foundation ( 2015-05-106 to E.D.). L.M.K. is a trainee of the UC Davis MCB T32 Training Program (award GM007377 ). SynDIG4 KO mice were generated using the UC Davis Mouse Biology Program.

Funding Information:
Funding was provided by the American Heart Association (11POST7020009 to L.M.), Brain & Behavior Research Foundation NARSAD Young Investigator (grant 20748 to L.M.), United States-Israel Binational Science Foundation (BSF; grant 2012781 to Y.S.-B.) and the United States National Science Foundation (NSF; grant 1322302 to E.D.), NIH (R01 MH097887 to J.W.H., R01 NS078792 to J.W.H., U54 HD079125 MCP to J.L.S. and J.N.C.) and NIH New Director's Innovator Award Program (DP2 OD006479-01 to E.D.), UC Davis Academic Senate Research Program Pilot Grant (to E.D.), and Whitehall Foundation (2015-05-106 to E.D.). L.M.K. is a trainee of the UC Davis MCB T32 Training Program (award GM007377). SynDIG4 KO mice were generated using the UC Davis Mouse Biology Program.

Publisher Copyright:
© 2018 The Authors

Keywords

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

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