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 Somatostatin (Sst) Sst_Chodl subtype, the long-range GABAergic projecting neurons. Despite developmental onset of perturbations, functional 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 Sst_Chodl as the only 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 vulnerable targets in a model of neuropsychiatric risk factor.