A study identifies a coordinated gene-expression program between cortical neurons and astrocytes, termed SNAP, which declines in schizophrenia and aging. Using single-nucleus RNA sequencing of the prefrontal cortex from 191 donors, researchers found that in individuals with stronger synaptic gene expression in neurons, astrocytes showed increased expression of synaptic and cholesterol-related genes. This program, SNAP, is associated with cognitive flexibility and plasticity, which are impaired in schizophrenia and aging. Both conditions led to reduced SNAP expression in neurons and astrocytes. The study highlights the role of SNAP in normal interindividual variation and potential pathophysiology. It also shows that SNAP involves genes linked to schizophrenia risk and is influenced by age. The study further reveals that astrocytes and neurons exhibit coordinated gene-expression changes, with astrocytes contributing to synaptic function and cholesterol biosynthesis. The findings suggest that SNAP may be a key factor in cognitive and synaptic dysfunction in schizophrenia and aging, and that targeting this program could offer therapeutic potential. The study also emphasizes the importance of natural variation in understanding brain function and disease mechanisms.A study identifies a coordinated gene-expression program between cortical neurons and astrocytes, termed SNAP, which declines in schizophrenia and aging. Using single-nucleus RNA sequencing of the prefrontal cortex from 191 donors, researchers found that in individuals with stronger synaptic gene expression in neurons, astrocytes showed increased expression of synaptic and cholesterol-related genes. This program, SNAP, is associated with cognitive flexibility and plasticity, which are impaired in schizophrenia and aging. Both conditions led to reduced SNAP expression in neurons and astrocytes. The study highlights the role of SNAP in normal interindividual variation and potential pathophysiology. It also shows that SNAP involves genes linked to schizophrenia risk and is influenced by age. The study further reveals that astrocytes and neurons exhibit coordinated gene-expression changes, with astrocytes contributing to synaptic function and cholesterol biosynthesis. The findings suggest that SNAP may be a key factor in cognitive and synaptic dysfunction in schizophrenia and aging, and that targeting this program could offer therapeutic potential. The study also emphasizes the importance of natural variation in understanding brain function and disease mechanisms.