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

Abstract

Neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (SCZ) share genetic risk factors, including rare high penetrance single nucleotide variants and copy number variants (CNVs), and 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 critical nexus for cognitive deficits across these disorders. Notably, genes within 22q11.2 deletions, known to confer a high risk of SCZ, ASD, and cognitive impairment, showed a strong expression bias toward vasoactive intestinal peptide-expressing cells (VIP+) among CGE subtypes. To explore VIP+ GABAergic interneuron perturbations 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.