SULT4A1 Modulates Synaptic Development and Function by Promoting the Formation of PSD-95/NMDAR Complex

Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase that is highly conserved across species and extensively expressed in the brain. However, the biological function of SULT4A1 is unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as Phelan-McDermid syndrome and schizophrenia. Here, we investigate the role of SULT4A1 within neuron development and function. Our data demonstrate that SULT4A1 modulates neuronal branching complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively regulating the catalytic activity of Pin1 toward PSD-95, facilitates NMDAR synaptic expression and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the pathologic phenotypes of neurons knocked down by SULT4A1 by specifically restoring dendritic spine density and rescuing NMDAR-mediated synaptic transmission. Together, these findings identify SULT4A1 as a novel player in neuron development and function by modulating dendritic morphology and synaptic activity.SIGNIFICANCE STATEMENT Sulfotransferase 4A1 (SULT4A1) is a brain-specific sulfotransferase highly expressed in neurons. Different evidence has suggested that SULT4A1 has an important role in neuronal function and that SULT4A1 altered expression might represent a contributing factor in multiple neurodevelopmental disorders. However, the function of SULT4A1 in the mammalian brain is still unclear. Here, we demonstrate that SULT4A1 is highly expressed at postsynaptic sites where it sequesters Pin1, preventing its negative action on synaptic transmission. This study reveals a novel role of SULT4A1 in the modulation of NMDA receptor activity and strongly contributes to explaining the neuronal dysfunction observed in patients carrying deletions of SULTA41 gene.