Exploring hippocampal dysfunction in schizophrenia with pluripotent stem cell models.

Schizophrenia is a complex neurodevelopmental disorder characterized by widespread cognitive and behavioral impairments, with the hippocampus playing a critical role in its pathophysiology. While traditional approaches such as animal models and postmortem studies have provided valuable insights, they fall short in capturing the human-specific and developmental features of the disease. Human pluripotent stem cell (hPSC) models, particularly 3D brain organoids, represent a powerful new tool for investigating the cellular and circuit-level mechanisms underlying schizophrenia. Although cortical and striatal organoids have been increasingly utilized in psychiatric research, hippocampal organoid models remain underdeveloped and underused. This review outlines the developmental basis of hippocampal dysfunction in schizophrenia and discusses the emergence of hPSC-derived hippocampal organoids and assembloids as novel in vitro systems. We highlight key findings from the limited studies using hippocampal differentiations in schizophrenia, explore their potential to model region-specific circuitry (e.g., DG-CA3, cortico-hippocampal, and hippocampalstriatal networks), and identify major technical challenges such as the absence of CA1/CA2 subfields, limited vascularization, and the need for microglial integration. Finally, we propose future directions to refine these models and leverage them for mechanistic discovery and therapeutic screening. By integrating genetic, imaging, and developmental perspectives, this review positions hippocampal organoid technology as a promising yet underutilized platform for advancing our understanding of schizophrenia's neurodevelopmental origins.