Rare mutations implicate CGE interneurons as a vulnerable axis of cognitive deficits across psychiatric disorders

Neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (SCZ) share genetic risk factors, including genes affected by rare high-penetrance single nucleotide variants (SNVs) and copy number variants (CNVs). ASD and SCZ exhibit both overlapping and distinct clinical phenotypes. Cognitive deficits and intellectual disability--critical predictors of long-term outcomes--are common to both conditions. To investigate shared and disorder-specific neurobiological impact of highly penetrant rare mutations in ASD and SCZ, we analyzed human single-nucleus whole-brain sequencing data to identify strongly affected brain cell types. Our analysis revealed caudal ganglionic eminence (CGE)-derived GABAergic interneurons as a key nexus for cognitive deficits across these disorders. Notably, genes within 22q11.2 deletions, known to confer a high risk for SCZ, ASD, and cognitive impairment, showed a strong expression bias toward vasoactive intestinal peptide-expressing cells (VIP+) among CGE subtypes. To explore perturbations of VIP+ GABAergic interneurons in the 22q11.2 deletion syndrome in vivo, we examined their activity in the Df(16)A+/- mouse model during a spatial navigation task and observed reduced activity along with altered responses to random rewards. At the population level, VIP+ interneurons exhibited impaired spatial encoding and diminished subtype-specific activity suggesting deficient disinhibition in CA1 microcircuits in the hippocampus, a region essential for learning and memory. Overall, these results demonstrate the crucial role of CGE-derived interneurons in mediating cognitive processes that are disrupted across a range of psychiatric and neurodevelopmental disorders.