A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms

SIMPLE SUMMARY: Impairment of the immune-barrier system in the aged brain is manifested in neurodegenerative diseases, such as Alzheimer’s disease. Cerebrospinal fluid flow and drainage system of meningeal lymph scavenge the waste products in the brain parenchyma. Recent accumulating attention to the immune system in the brain is now accompanied by the expanding knowledge of the breakdown mechanism of the blood-brain barrier and increased permeability of activated immune cells at the glymphatic system, in developing brains, and in the situation of infections. These disruptions of the immune-barrier function between vasculature and brain parenchyma, where neurons locate, would also occur by infection of viruses or microorganisms, vascular injury, cerebral hemorrhage, neurological diseases, and other external factors like stress. Those activate microglia, brain-resident immune cells, and allow the infiltration of immune cells, such as macrophages, neutrophils, and T cells. Aberrant immunity disrupts the functions of neurons and prevents the maturation of glia (e.g., oligodendrocytes and astrocytes), which may cause the emergence of the highly variable psychiatric symptoms seen in schizophrenia, autism spectrum disorders, Alexander disease, and developmental disorders via an abnormality of brain activities at both cellular and organism levels. Therefore, this hypothesis challenges the longstanding neuron-centric view of neurodegenerative and psychiatric diseases. ABSTRACT: The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain. Recent notions from studies of postmortem brains and clinical studies of neurodegenerative diseases, infection, and cerebral hemorrhage, implied that the breakdown of those barrier systems and infiltration of activated immune cells disrupt the function of both neurons and glia in the parenchyma (e.g., modulation of neurophysiological properties and maturation of myelination), which causes the abnormality in the functional connectivity of the entire brain network. Due to the vulnerability, such dysfunction may occur in developing brains as well as in senile or neurodegenerative diseases and may raise the risk of emergence of psychosis symptoms. Here, we introduce this hypothesis with a series of studies and cellular mechanisms.