Dysfunction of cortical GABAergic projection neurons as a major hallmark in a model of neuropsychiatric syndrome.

Neuropsychiatric disorders have a strong genetic component and are linked to developmental risk factors, yet it is unclear why symptoms appear only later in life and which neuronal types contribute to brain dysfunction. We addressed these questions using a robust mouse model of a neuropsychiatric syndrome-the 15q13.3 microdeletion. Single-nucleus transcriptomics revealed the largest gene expression alterations in the somatostatin (Sst) Sst_Chodl subtype, the long-range γ-aminobutyric acid (GABAergic) projecting neurons. Despite the developmental onset of perturbations, impairments in Sst_Chodl neurons manifested only at late maturation. Calcium imaging and patch-clamp recordings unraveled impaired responsivity overall in deep-layer Sst neurons, with only the Sst_Chodl subtype exhibiting increased activity. Patch-seq analysis connected molecular changes to cellular dysfunction of Sst_Chodl neurons. Finally, microdeletion mice displayed sleep disturbances associated with impaired activity of deep-layer Sst neurons, which were rescued by chemogenetic inhibition of Sst_Chodl neurons. Our findings spotlight GABAergic projection neurons as potential vulnerable targets in neuropsychiatric disorders.