NMDA receptor subunit composition controls synaptogenesis and synapse stabilization

Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5855-60. doi: 10.1073/pnas.1012676108. Epub 2011 Mar 22.

Abstract

During early postnatal development in the rat hippocampus, synaptogenesis occurs in parallel with a developmental switch in the subunit composition of NMDA receptors from NR2B to NR2A. It is unclear how this switch affects the process of synaptogenesis, synapse maturation, and synapse stabilization. We investigated the role of NR2 subunits in synaptogenesis during the period in which expression and synaptic incorporation of the NR2A protein begins through the time when it reaches adult levels. We found that early expression of NR2A in organotypic hippocampal slices reduces the number of synapses and the volume and dynamics of spines. In contrast, overexpression of NR2B does not affect the normal number and growth of synapses; however, it does increase spine motility, adding and retracting spines at a higher rate. The C terminus of NR2B, and specifically its ability to bind CaMKII, is sufficient to allow proper synapse formation and maturation. Conversely, the C terminus of NR2A was sufficient to stop the development of synapse number and spine growth. Our results indicate that the ratio of synaptic NR2B over NR2A controls spine motility and synaptogenesis, and suggest a structural role for the intracellular C terminus of NR2 in recruiting the signaling and scaffolding molecules necessary for proper synaptogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Gene Expression Regulation, Developmental / physiology*
  • Hippocampus / growth & development*
  • Microscopy, Fluorescence
  • Protein Subunits / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Statistics, Nonparametric
  • Synapses / metabolism
  • Synapses / physiology*

Substances

  • Protein Subunits
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2