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.
Highlights
In the mammalian CNS, most excitatory neurotransmission takes place at spiny synapses, and our understanding of the mechanisms that control the density and strength of excitatory glutamatergic synapses remains incomplete
PlexinA2 is a novel receptor for Sema5A, and we show that loss of Sema5A leads to increased excitatory synaptic transmission and autism-spectrum disorders (ASD)-like behavioral phenotypes
We demonstrate here that Sema5A is a novel inhibitor of excitatory synapse formation and AMPAtype synaptic transmission
Summary
In the mammalian CNS, most excitatory neurotransmission takes place at spiny synapses, and our understanding of the mechanisms that control the density and strength of excitatory glutamatergic synapses remains incomplete. Many synaptogenic molecules have been identified that can induce preor postsynaptic differentiation (Allen and Barres, 2005; Shen and Cowan, 2010; Siddiqui and Craig, 2011; de Wit et al, 2011). Precise regulation of CNS synapse density is critical for proper brain function and mental health, and imbalances in excitatory and inhibitory synaptic transmission are associated with neurodevelopmental disorders such as autism-spectrum disorders (ASD) and schizophrenia (Penzes et al, 2011). Proper insertion of adult-born granule cells (GCs) into a pre-existing synaptic network offers a unique opportunity to study mechanisms governing axon guidance, dendrite elaboration and formation of synaptic contacts that contribute to neuronal plasticity in mature nervous tissue. Despite recent progress (Tran et al, 2009; Siddiqui et al, 2013; de Wit et al, 2013), our
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