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

Cell Rep. 2018 Feb 27;22(9):2246-2253. doi: 10.1016/j.celrep.2018.02.026.

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.

Keywords: LTP; NG5; Prrt1; SynDIG family; SynDIG4; auxiliary factor; excitatory synapse; extrasynaptic AMPARs; hippocampus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cognition*
  • Excitatory Postsynaptic Potentials*
  • Female
  • Genes, Reporter
  • Hippocampus / metabolism
  • Kinetics
  • Long-Term Potentiation
  • Membrane Proteins / metabolism*
  • Memory
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity*
  • Protein Subunits / metabolism
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*
  • Task Performance and Analysis
  • Xenopus laevis

Substances

  • Membrane Proteins
  • Nerve Tissue Proteins
  • Protein Subunits
  • Prrt1 protein, mouse
  • Receptors, AMPA