GENETIC RISK ANALYSES HIGHLIGHT PARVALBUMIN-EXPRESSING INTERNEURON WIRING DURING DEVELOPMENT AS A VULNERABLE PROCESS IN SCHIZOPHRENIA

Schizophrenia is a severe, disabling neurodevelopmental disorder that has been extensively studied neurobiologically. Despite decades of research, the underlying pathophysiological mechanisms remain unclear, hindering the development of effective treatments. Recent large-scale human genomic studies have identified disrupted neuronal function, mainly linked to changes in synaptic connectivity. However, these studies mainly focus on adult schizophrenia patients, offering limited insights into the disorder's developmental origins. Thus, the precise mechanisms by which genetic alterations cause the disorder are unknown. By combining data from large-scale genomic research and cell-type-specific transcriptomics across development, we demonstrate that parvalbumin-expressing(PV+) basket cells (PVBCs) are vulnerable to schizophrenia-related genetic risk during early postnatal development. Specifically, our analyses highlight the wiring of these cells as a process particularly sensitive. To explore this idea, we conducted cell-type-specific loss-of-function experiments in mice during postnatal development. We found that representative genes in the subset enriched in schizophrenia genetic risk (TENM1 and PPARGC1A) influence PVBC synapse formation in the cortex. Moreover, similar manipulation of genes outside this subset but strongly associated with schizophrenia (SETD1A and NXPH1) also caused significant deficits in PVBC synapses. Noteworthy, our genetic manipulations not only disrupt the wiring of PV+ interneurons, but lead to abnormal gamma oscillations in cortical circuits, a well-known hallmark of the disease. Altogether, our findings reveal a crucial cellular mechanism underlying the complex genetic architecture of schizophrenia, emphasizing the integration of PVBCs in cortical circuits as a vulnerable process to genetic risk. This provides a mechanistic framework for developing targeted therapeutic strategies for the disorder.