Breaching the blood-brain barrier as a gate to psychiatric disorder

Hadar Shalev, Yonatan Serlin, Alon Friedman, Hadar Shalev, Yonatan Serlin, Alon Friedman

Abstract

The mechanisms underlying the development and progression of psychiatric illnesses are only partially known. Clinical data suggest blood-brain barrier (BBB) breakdown and inflammation are involved in some patients groups. Here we put forward the "BBB hypothesis" and abnormal blood-brain communication as key mechanisms leading to neuronal dysfunction underlying disturbed cognition, mood, and behavior. Based on accumulating clinical data and animal experiments, we propose that events within the "neurovascular unit" are initiated by a focal BBB breakdown, and are associated with dysfunction of brain astrocytes, a local inflammatory response, pathological synaptic plasticity, and increased network connectivity. Our hypothesis should be validated in animal models of psychiatric diseases and BBB breakdown. Recently developed imaging approaches open the opportunity to challenge our hypothesis in patients. We propose that molecular mechanisms controlling BBB permeability, astrocytic functions, and inflammation may become novel targets for the prevention and treatment of psychiatric disorders.

Figures

Figure 1
Figure 1
The BBB Hypothesis of Psychiatric Disorders. Interactions within the neurovascular unit in the presence of abnormal blood-brain communication. BBB breakdown results in the diffusion of serum proteins (e.g., albumin, see text) into the brain, activation of signaling pathways, and inducing the transformation of astrocytes. This “reactive” glial reaction is associated with impaired extracellular homeostasis (e.g., reduced buffering of extracellular potassium and glutamate) and a local inflammatory response (e.g., secretion of cytokines, activation of microglia) and is enhanced in the presence of an inflammation in the periphery. Together, neuronal network dysfunction develops due to pathological synaptic plasticity.

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