How Does Altered Function of the Hippocampus Contribute to the Development of Psychosis?

In this review, we explore the critical role of hippocampal dysfunction in the pathophysiology of psychosis, focusing on translational insights from 22q11.2 deletion syndrome (22q11DS). Converging evidence indicates that individuals with 22q11DS, one of the highest genetic risk factors for schizophrenia, exhibit a shared neurobiological vulnerability with idiopathic psychosis, characterized by cognitive decline and atypical brain development, particularly within the hippocampus. Here, we explore translational evidence for hippocampal dysfunction in humans with 22q11DS and the homologous mouse models at different scales. At the neuronal level, deficits include impaired neural migration, reduced dendritic spine density of pyramidal neurons, and decreased neurogenesis. These deficits contribute to circuit-level alterations such as altered glutamatergic transmission and impaired long-term potentiation, leading to memory impairment. Moreover, hypoexcitability of parvalbumin-positive interneurons (PVIs) disrupts gamma-band oscillations in the hippocampus. At the network level, reduced hippocampal-prefrontal synchrony and hypoconnectivity are observed in both mouse models and humans with 22q11DS. These findings support a model in which neurodevelopmental deficits in neural migration result in circuit dysfunction, which impacts large-scale neural dynamics and cognition. Crucially, hippocampal-prefrontal hypoconnectivity and imbalances between excitatory and inhibitory neurotransmitters are exacerbated in 22q11DS carriers with psychotic symptoms. Studies targeting dendritic spine density and PVI function in 22q11DS mouse models have shown potential for reversing neural and cognitive deficits, suggesting new therapeutic strategies. The effectiveness of these treatments varies with age, highlighting the need to identify critical developmental windows for intervention. In conclusion, this review emphasizes the hippocampus as a target for understanding and treating psychotic disorders.