Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells

Elife. 2014 Oct 14;3:e04390. doi: 10.7554/eLife.04390.

Abstract

Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A-/- GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A-/- mutants, PlexinA2-/- mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A-/- mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.

Keywords: 3D electron microscopy; dentate granule cells; hippocampus; mouse; neuroscience; plexin; semaphorin; synaptogenesis.

Publication types

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

MeSH terms

  • Aging / metabolism*
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Dendritic Spines / metabolism
  • Dentate Gyrus / metabolism*
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis*
  • Post-Synaptic Density / metabolism
  • Protein Binding
  • Rats
  • Semaphorins / metabolism*
  • Social Behavior
  • Synapses / metabolism*
  • Synaptic Transmission

Substances

  • Membrane Proteins
  • Nerve Tissue Proteins
  • Sema5A protein, mouse
  • Semaphorins
  • semaphorin 5A, rat