STXBP5/tomosyn regulates both the small Rho GTPase and the surface expression of AMPA receptors to control the dendritic stability of neurons

Tomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, regulates neurotransmitter release, synaptic transmission, and partitioning of synaptic vesicle pools. However, the role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. In this study, we have shown that knockdown of tomosyn in mouse primary neurons leads to an increase of RhoA GTPase activity accompanied by compromised dendritic arborization and loss of dendritic spines. Inhibiting RhoA signaling was sufficient to rescue the abnormal dendritic morphology. Tomosyn knockdown neurons also exhibited reduced miniature excitatory postsynaptic current (mEPSC) frequency. Additionally, aberrant surface expression of AMPA receptors was observed in tomosyn-deficient neurons. These findings suggest that tomosyn regulates dendritic stability through two mechanisms: 1) tomosyn functions as a RhoA inhibitor for the maintenance of dendritic arborization and dendritic spine stability; 2) tomosyn acts as a component of dendritic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) accessory proteins to regulate trafficking of glutamate receptors. Recent studies have shown that deletion and mutations of STXBP5 are associated with autism spectrum disorder (ASD). Neurons expressing two autism-associated tomosyn variants, L412V or Y502C, were further examined and displayed loss-of-function phenotypes, including reduced dendritic complexity and spine density as well as decreased surface expression of AMPA receptors. This study uncovers a novel role of tomosyn in maintaining neuronal function, and also a potential pathway to explain the cellular pathology underlying tomosyn-associated ASD.