The gatekeepers breached: claudin dysregulation in psychiatric disorders

Psychiatric disorders such as depression, bipolar disorder, schizophrenia, and autism spectrum disorder are increasingly understood not only as disruptions in brain chemistry or circuitry but also as disorders of neural microenvironments and barriers. This review explores the critical role of claudins, transmembrane proteins that form tight junctions, in maintaining the integrity of the blood - brain barrier (BBB) and other brain structures. Claudin-5, prominently expressed in the BBB, and claudin-11, essential for myelin integrity, emerge as central players in psychiatric pathophysiology. Evidence from human postmortem studies, serum biomarkers, and animal models indicates that claudin-5 is downregulated in key brain regions in depression, bipolar disorder, and schizophrenia, contributing to BBB permeability and facilitating neuroinflammation. Similarly, claudin-11 deficits in schizophrenia suggest impaired myelination and disrupted neural connectivity. In autism and ADHD, altered tight junction protein profiles imply more subtle or context-dependent barrier dysfunction. Mechanistically, claudin dysregulation permits peripheral inflammatory mediators and immune molecules to access brain tissue, triggering neuroinflammation, oxidative stress, and synaptic dysfunction. Additionally, loss of myelin barrier function may impair signal timing and synchronization. These findings support a unifying hypothesis: that barrier dysfunction, mediated by claudin disruption, underlies diverse psychiatric symptoms by destabilizing the brain's protected environment. Recognizing the role of claudins in mental illness opens avenues for novel biomarker development and therapeutic strategies aimed at restoring barrier integrity, offering a new perspective on the intersection of neurobiology and psychiatry.