Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling

J Neurosci. 2014 Aug 20;34(34):11274-87. doi: 10.1523/JNEUROSCI.1774-14.2014.


Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits.

Keywords: NrCAM; cell adhesion; cortical pyramidal neurons; semaphorin; spine morphogenesis; visual cortex.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Brain / cytology*
  • Brain / embryology
  • Brain / growth & development
  • Cell Adhesion Molecules / deficiency
  • Cell Adhesion Molecules / physiology*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dendritic Spines / physiology*
  • Dendritic Spines / ultrastructure
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA Antagonists / pharmacology
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Neurons / ultrastructure*
  • Sodium Channel Blockers / pharmacology
  • Subcellular Fractions / metabolism
  • Subcellular Fractions / ultrastructure


  • Cell Adhesion Molecules
  • GABA Antagonists
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Nrcam protein, mouse
  • Sema3f protein, mouse
  • Sodium Channel Blockers
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins