Blood-brain barrier regulation in psychiatric disorders

Abstract

The blood-brain barrier (BBB) is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain. Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion whereas transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion. Here, we review the evidence that perturbation of these processes may underlie the development of psychiatric disorders including schizophrenia, autism spectrum disorder (ASD), and affective disorders. Increased permeability of the BBB appears to be a common factor in these disorders, leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress. However, although there is no common mechanism underpinning BBB dysfunction even within each particular disorder, the tight junction protein claudin-5 may be a clinically relevant target given that both clinical and pre-clinical research has linked it to schizophrenia, ASD, and depression. Additionally, we discuss the clinical significance of the BBB in diagnosis (genetic markers, dynamic contrast-enhanced-magnetic resonance imaging, and blood biomarkers) and in treatment (drug delivery).

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

“…It is unclear whether all 22qDS patients present with compromised barrier function, impaired claudin-5 structure, and elevated ICAM-1 expression, which together may contribute to the increased risk for neuropsychiatric conditions in this population, or whether these results are only evident in 22qDS patients that develop SZ. As our murine data indicate BBB dysfunction in naïve 22qDS mice, we hypothesize that our results are conferred by the deletion alone, regardless of SZ diagnosis, and therefore may contribute to the increased susceptibility to SZ and other neuropsychiatric disorders in 22qDS (Fiksinski et al, 2018;Fiorentino et al, 2016;Gandal et al, 2018;Kealy et al, 2018;Schneider et al, 2014), but future studies including a 22qDS without SZ group will be important to address these questions.…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…In addition to the neurodegenerative diseases, vascular problems are also observed following traumatic brain injury (TBI) and in neuropsychiatric disorders (for review see [121]). BBB disruptions occur in TBI [122,123], which may contribute to the more long-term neurological problems in TBI.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…Interestingly, serum OxS determinations correlate with the occurrence and course of schizophrenia, which suggests that OxS in CSN occurs earlier which may be identified already in the early stages of the ongoing pathology. In addition, OxS data correlate with indicators of damaged BBB in schizophrenic patients, which combines the concept of oxidative stress and neuritis [128] with the pathogenesis of schizophrenia [253,254]. Morphological changes in the structure of capillaries and cells of the neurovascular unit (NVU) occur in the prefrontal and visual cortex of schizophrenic patients, along with vacuole destruction of endothelial cells, astrocyte-foot processes, and the reduction of baseline membrane thickness [254] (Figures 2 and 3).…”