Tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors.
Abstract
Tomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, has a well-established presynaptic role in the inhibition of neurotransmitter release and the reduction of synaptic transmission by its canonical interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery. However, the postsynaptic role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. We used short hairpin RNA to knock down tomosyn in mouse primary neurons to evaluate the postsynaptic cellular function and molecular signaling regulated by tomosyn. Knockdown of tomosyn led to an increase of RhoA GTPase activity accompanied by compromised dendritic arborization, loss of dendritic spines, decreased surface expression of AMPA receptors, and reduced miniature excitatory postsynaptic current frequency. Inhibiting RhoA signaling was sufficient to rescue the abnormal dendritic morphology and the surface expression of AMPA receptors. The function of tomosyn regulating RhoA is mediated through the N-terminal WD40 motif, where two variants each carrying a single nucleotide mutation in this region were found in individuals with autism spectrum d...Continue Reading
References
The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis
Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation
Visualization of small GTPase activity with fluorescence resonance energy transfer-based biosensors.
Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders
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