Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells
- University of Michigan School of Medicine, United States
- Johns Hopkins University School of Medicine, United States
- University of North Carolina, United States
Abstract
Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene, however its function in brain development is unknown. Here 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- and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.
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Ethics
Animal experimentation: All mice used in this study were housed and cared for in accordance with NIH guidelines, and all research conducted was done with the approval of the University of Michigan Medical School (UCUCA protocols PRO00002466 and PRO00001645) and The Johns Hopkins University (MO14M50 and MO12M381) Committees on Use and Care of Animals. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
© 2014, Duan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells
eLife 3:e04390.
https://doi.org/10.7554/eLife.04390
