Cell Reports, September 23, 2025
NICO Research Group: Neuropsychopharmacology
Morellato A§, De Gregorio M§, Angelini C§, Torelli F, Belmonte V, Alfieri A, Bersia B, Cravero T, Gai M, Bianciotto OT, Oddone R, Salemme V, Natalini D, Centonze G, Nigrelli F, Raspanti A, Gurgone A, D’Attanasio G, Mele P, Eva C, Lodi A, Gavello D, Carabelli V, Hidisoglu E, Chiantia G, Carbone E, Becchetti A, Giustetto M, Marcantoni A, Turco E, Bertocchi I*, Defilippi P* (2025). The adaptor protein SKT interacts with PSD-95 and SHANK3 and affects synaptic functions. Cell Reports, 44, 116206, September 23, 2025. IF 6.9
Highlights
• SKT is a postsynaptic scaffold interacting directly with PSD95 and SHANK3
• SKT loss causes defects in dendritic spine formation, morphology, and maturation
• SKT loss leads to a significant reduction in excitatory synaptic transmission
• SKT-KO mice exhibit impaired motor, cognitive, and executive functions
Summary
Postsynaptic density (PSD) is a tightly interconnected protein network ensuring synaptic function through the interaction of neurotransmitter receptors, structural adaptor proteins, and signaling molecules. Disruption of PSD may cause neurological diseases, including autism spectrum disorders and cognitive impairment. We demonstrate that the SKT adaptor distinctly localizes within dendritic spines as an integral component of the synaptic network, binding PSD-95 and SHANK3. SKT-knockout (KO) mice show significant abnormalities in dendritic spine density and morphology, consistent with RhoA and Rac1 GTPase dysregulated activity. KO-derived neuronal cultures display delayed neuronal synchronization and maturation associated with glutamatergic pre- and postsynaptic impairment. Behavioral tests on KO mice reveal increased self-grooming activity and impaired motor coordination, with altered cognitive and executive functions compared to wild-type mice. Overall, SKT emerges as a key contributor to the structural and functional PSD organization, regulating synaptic function through its interactions with PSD components.