Perfluorinated compounds (PFCs) are organofluorine compounds containing carbon-fluorine and carbon-carbon bonds. They are used as water and oil repellants in clothes and pharmaceutical tablets, but have been found to cause neurotoxicity. However, it remains elusive whether PFCs affect neural survival or activity, or whether they alter different neuronal regulations in the brain. Additionally, there is a paucity of data on the regulatory mechanisms involved in PFCs-induced neural toxicity.In the current study, we report that PFOA or PFHpA differentially alter neural survival and activity in primary cortical neurons. PFOA exposure induces neural apoptosis in cortical neurons, while PFHpA does not significantly induce apoptosis. However, PFHpA exposure alters dendritic spine morphogenesis and synaptic formations in primary cortical neurons. Furthermore, we observed that PFHpA activates neural activity and synaptic transmission in primary cortical neurons. Intriguingly, PFOA exposure impairs neural activity by inhibiting dendritic spine maturation.Our findings reveal a novel mechanism by which PFCs (PFHpA or PFOA) induce selective changes in dendritic spine morphogenesis and synapse formation. This could provide insights into the cellular basis for the abnormal behaviors observed in PFCs exposure.Funding Source: This work was supported by a grant from the Korea Institute of Toxicology (1711195885).