Analysis of 22q11.2 deletion syndrome reveals hippocampal dysfunction as a central mechanism in psychosis development. Individuals with this genetic condition show impaired neural migration, reduced dendritic spine density in pyramidal neurons, and decreased neurogenesis. These cellular deficits cascade into circuit-level problems including altered glutamatergic transmission, impaired long-term potentiation, and disrupted gamma-band oscillations due to hypoexcitable parvalbumin-positive interneurons.
This research provides crucial mechanistic insight into how genetic vulnerability translates into psychiatric symptoms. The hippocampus-prefrontal connectivity disruption observed in both mouse models and human patients suggests a conserved pathway from neurodevelopment to psychosis. For mental health, these findings point toward earlier intervention targets, potentially before full psychotic symptoms emerge. The excitatory-inhibitory imbalance identified here aligns with broader theories of schizophrenia pathophysiology, but the specific hippocampal focus offers more precise therapeutic targets. While 22q11.2 deletion syndrome affects only a subset of schizophrenia cases, the neurobiological mechanisms identified likely apply more broadly to idiopathic psychosis, making this work relevant for understanding the general population's psychiatric risk.