¹Tokyo Metropolitan Institute of Medical Science, Department of Basic Medical Sciences, Tokyo, Japan

Background: 

Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder often require long-term treatment after onset, highlighting the need for robust strategies for prediction and prevention. A shared post-onset feature across these conditions is reduced cerebral blood flow (CBF) in the prefrontal cortex. In addition, our postmortem analyses revealed disorder-specific capillary pathology in the prefrontal cortex, marked by fibrin accumulation, consistent with compromised microvascular integrity. Given the markedly increased cardiovascular mortality in these patient populations, these observations support the notion that microvascular dysfunction may be a key contributor to disease pathophysiology.

Aims & Objectives: We further hypothesize that microvascular dysfunction contributes not only to symptom-related pathophysiology but also to processes that initiate psychiatric disorders. In this study, we aim to evaluate whether retinal microvascular function—quantified by retinal blood flow measurements—can serve as a clinically feasible biomarker for predicting psychiatric disorder onset.

Method: We employed two genetic mouse models predisposed to psychiatric disorders: Disrupted-in-schizophrenia 1 (Disc1) heterozygous knockout mice and SET domain containing 1A (Setd1a) heterozygous knockout mice. To capture early changes prior to persistent behavioral phenotypes, we analyzed animals at 4 weeks of age. Mice underwent a behavioral battery, after which capillary structure in the medial prefrontal cortex—including vessel diameter and density—was quantified by image analysis. Retinal perfusion was monitored in real time using laser speckle flowgraphy. Wild-type mice served as controls.

Results: At 4 weeks of age, Disc1 and Setd1a heterozygous knockout mice showed behavioral abnormalities, including a transient reduction in prepulse inhibition (PPI) and impaired working memory; these changes were no longer evident by 6 weeks. Compared with wild-type controls, both models exhibited significant capillary dilation in the medial prefrontal cortex. Retinal capillary blood flow velocity was also reduced compared with controls.

Discussion & Conclusions: Across two independent models, we identified convergent microvascular abnormalities during the pre-onset phase—capillary structural changes in the medial prefrontal cortex together with reduced retinal perfusion. These findings suggest a shared vulnerability of the microvascular system early in disease progression. Because retinal blood flow can be measured non-invasively, it may provide a clinically feasible approach for early risk stratification and detection in humans. Future work will dissect the mechanisms linking brain and retinal capillary changes, with the goal of revealing early pathogenic processes that precede psychiatric disorder onset.