Microglia dysfunction in schizophrenia: an integrative theory

Medical Hypotheses (2000) 54(2), 198–202 © 2000 Harcourt Publishers Ltd DOI: 10.1054/mehy.1999.0018, available online at http://www.idealibrary.com on

Microglia dysfunction in schizophrenia: an integrative theory N. A. Munn Behavioral Health Clinic of St Peter’s Hospital, Helena, MT, USA

Summary Schizophrenia is a devastating illness of unknown etiology. It is characterized by increased brain ventricular volume, suggesting a progressive neurodevelopmental condition. There is evidence suggesting a correlation between in utero viral exposure and subsequent occurrence of schizophrenia. Many neurotransmitter systems have been implicated as being dysfunctional in schizophrenia. There are also data suggesting immune system dysfunction in schizophrenia, and a negative correlation between schizophrenia and rheumatoid arthritis. Microglia are phagocytic immune cells in the central nervous system (CNS) derived from peripheral blood monocytes. They are involved in brain development, neuroproliferative and neurodegenerative activities, several CNS illnesses, and CNS viral immunity. They may also be involved in neurotransmitter regulation. The current theory postulates microglial dysfunction initiated by early CNS viral exposure results in the abnormal neural development and neurotransmitter dysfunction seen in schizophrenia. © 2000 Harcourt Publishers Ltd

INTRODUCTION Schizophrenia is a devastating illness, often striking individuals in the prime of life and leading to years of disability. While there have been many hypothesis on its etiology, including neurotransmitter dysfunction, in utero viral exposure, and genetic vulnerability, there is not to date a unifying theory. Microglia, believed to originate from peripheral blood monocytes as they are morphologically, immunophenotypically and functionally related to cells of the monocyte/macrophage lineage, are felt to be the intrinsic immuneffector cell of the brain (1). Microglia are ubiquitously distributed in the CNS and comprise up to 20% of the total glial cell population in the brain (2). They have in recent years been shown to be involved in many CNS illnesses including multiple sclerosis (3), Alzheimer’s disease (4), Pick’s disease (5), Huntington’s disease (6), and in wound healing after traumatic brain injury in adults (7). The current paper proposes an integrative theory of schizophrenia, postulating a microglial dysfunction.

Received 24 August 1998 Accepted 9 December 1998 Correspondence: Nathan A. Munn MD, Behavioral Health Clinic of St Peter’s Hospital, 2475 Broadway, Helena, MT 59601, USA. Phone: +1 406 444 2233; Fax: +1 406 447 2696

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Possible correlations between findings in schizophrenia and known microglial functions will be highlighted, including neurodevelopment, viral exposure, perinatal complications, neurotransmitter findings, immune system abnormalities, and relationships to rheumatoid arthritis. While the literature used in developing this theory is extensive, it by no means is meant to be a complete review of the literature for any of the specific items discussed. Neurodevelopmental findings in schizophrenia and microglia Several lines of evidence, including clinical, epidemiologic, neuropathological and imaging data suggest schizophrenia is a neurodevelopmental disorder. Patients with schizophrenia have a tendency toward premorbid abnormalities such as asociality, soft neurological signs, minor physical anomalies, and impaired cognitive and neuromotor functioning (8–12). It also is characterized by enlarged brain ventricles and cortical volume reduction (e.g. 13,14). Thus there is support for neurodevelopmental disorder theories of schizophrenia, and extrapolating from these data, several theories have been put forth (14–16), including abnormalities in the so called pruning process (17). Microglia have been shown to be involved in neurodevelopment and have also been shown to migrate into the

Microglia in schizophrenia

developing CNS very early (18,19). There is evidence for their neurotoxicity (20) and their role in stimulating neuronal growth (21). One role microglia seem to have in early neuronal development is the phagocytosis of dying neurons. In the developing brain, dendritic trees are ‘pruned’ in association with various developmental processes (22,23). Reports have been made concerning the role of microglia in this neuronal pruning process in the retina (24), the cerebellum (25) and the cortex (26). In addition, microglia interact with dopaminergic neurons via plasminogen, regulating dopaminergic neuronal cell growth and death (27). In utero viral exposure in schizophrenia and microglia The hypothesis that influenza may be an etiological factor in schizophrenia was first proposed by Karl Menninger in 1922 who noted that infection of a mature brain may be followed by the symptoms of schizophrenia. More recently, studies examining incidence of schizophrenia in individuals exposed to influenza epidemics while in the second trimester have supported this hypothesis. These studies include the Finnish cohort studies with long-term follow-up (28–30), and a southern hemisphere study (31). In addition, an association between central nervous system infections in childhood and adult onset schizophrenia has been reported (32). Microglia have also been shown to play a major role in CNS viral infections. These infections include human immunodeficiency virus (33,34), cytomegalovirus (35), murine retrovirus (36), and herpes simplex virus type I (37). Microglia have also been shown to activate memory T-lymphocyte responses to recall viral antigens including influenza (38).

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concentrations have been reported (46,47), and an increase in tumor necrosis factor (TNF) (47). Cellular immune system alterations have also been found including higher numbers of blast-type atypical lymphocytes (48), abnormal T-lymphocyte subset distribution in cerebrospinal fluid (49) and in acutely psychotic patients with schizophrenia (50), B-lymphocyte abnormalities of increased cyclic AMP response (51) and increased numbers of CD5+ B-lymphocytes (52), and decreased natural killer cell activity (53,54). Macrophages, cells involved in the initiation of many immune system functions including IL-1 and TNF production and stimulation of T-cells and B-cells (55), have been shown to have decreased function in schizophrenia (54). Macrophage derived microglia are involved in several immune functions. These include the release of neurotoxic compounds (i.e. nitric oxide or proteases) and inflammatory cytokines (i.e. IL-1, IL-6 and TNF), phagocytosis, and in the presentation of antigen to T-lymphocytes (1). Neurotransmitters, schizophrenia and microglia Several neurotransmitter systems have been implicated as abnormal in schizophrenia. These include the dopamine, norepinephrine, serotonin, GABA and neuropeptide systems (56). In addition to their role in neuronal cell growth and death, microglia have been shown to have enzyme activity modified by L-DOPA, norepinephrine, GABA, and acetylcholine (57). Tumoricidal activity of macrophages have been shown to be modulated by several neuropeptides (58), and microglia have been reported to produce beta-endorphin (59).

Perinatal complications in schizophrenia and microglia

Rheumatoid arthritis, schizophrenia and microglia

In addition to possible viral associations, perinatal complications have also been associated with adult onset schizophrenia (39–42). Microglia have also been shown to be involved in hypoxic-ischemic injury in neonatal brains (43,44).

Studies noting the negative correlation between schizophrenia and rheumatoid arthritis date back 50 years. Recent reviews of the data supporting this negative correlation have concluded that there is enough evidence to justify further research in this area (60, 61). A recent publication has put forth the notion that natural resistance genes may mediate this association (62). Macrophage, progenitor cells to microglia, have been shown to play a role in rheumatoid arthritis. They are believed to be one of the major antigen presenters in rheumatoid arthritis, to have a role in joint destruction, and to be important effector cells in their production of cytokines such as TNF and IL-1 (63,64).

Immune system abnormalities in schizophrenia and microglia Schizophrenia as an immune disorder has been suggested for many years. In 1967, Health et al. reported ‘antibrain globulins’ (45). More recently, reports of autoimmunity in schizophrenia have focused on increased prevalence of other autoimmune diseases, antinuclear antibodies and anticytoplasmic antibodies. Other reported immune abnormalities in schizophrenia have included a decrease in interleukin-2 (IL-2) production, and an increase in interleukin-6 (IL-6) © 2000 Harcourt Publishers Ltd

Microglial dysfunction as a cause of schizophrenia Thus, as can be seen, findings of abnormalities in schizophrenia closely parallel known functions of microglia. Medical Hypotheses (2000) 54(2), 198–202

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First, schizophrenia is often considered to be a neurodevelopmental illness, possibly an abnormality of neural pruning. Microglia have been shown to migrate into the CNS early in development and be involved in both neuronal growth and destruction, along with phagocytosis of dying neuronal bodies. Second, for many years a connection between viral infections and schizophrenia has been noticed, in particular influenza but other viruses have also been implemented. Microglia most likely are the first immune cells in the CNS to process viral infections and would be involved in viral phagocytosis and antigen presentation. They would perform this function regardless of the specific virus, thus may provide an explanation for the data on viral infections in schizophrenia. Third, patients suffering perinatal complications have a higher than normal incidence of schizophrenia later in life, and microglia have been shown to be a part of the immune reaction to ischemic brain trauma. Fourth, there have been many immune system abnormalities found in patients with schizophrenia including decreased IL-2, increased IL-6 and TNF, along with cellular immunity abnormalities including decreased phagocytic activity in macrophages. Microglia have been shown to produce IL6 and TNF, and are the macrophage-derived phagocytic cells in the CNS. Also, as the intrinsic immuneffector cell of the brain, microglia have a major role in the regulation of the overall immune reactivity of the CNS, including antigen presentation and T-cell modulation. Thus, a dysfunction in microglia could potentially explain the plethora of immune abnormalities reported in schizophrenia. Finally, the role of macrophages in rheumatoid arthritis suggest a potential explanation for the negative association between schizophrenia and rheumatoid arthritis. There could be a shared genetic loci between schizophrenia and rheumatoid arthritis which regulates macrophage/microglial function, resulting in abnormal microglial function in schizophrenia and macrophage dysfunction in rheumatoid arthritis. In summary, microglia dysfunction as an integrated theory of etiology in schizophrenia is as follows: in genetically susceptible individuals, early exposure to viruses or perinatal complications leads to microglial dysfunction resulting in abnormal pruning during neurodevelopment. This process may be analogous to rheumatic fever, where antibodies produced to Streptococcus also crossreact with heart tissue. This neurodevelopmental pruning abnormality would lead to the increased ventricular size and cortical volume reduction seen in schizophrenia. Once genetically susceptible microglia react to viral or damaged tissue antigen, they may ‘cross react’ to disturb normal neurodevelopment of dopamine, serotonin, and other neurotransmitter systems. In addition, abnormal microglia may then produce excess TNF and IL-6 and alter other measures of immune function seen in schizophrenia. Medical Hypotheses (2000) 54(2), 198–202

Of coarse, much research needs to take place to support or discredit this theory. Several lines of investigation are conceivable. Greater study on monocyte and macrophage activity in patients with schizophrenia needs to take place. Cultured macrophage could be studied as to their phagocytic properties, including phagocytosis of neuron cell products and neurotransmitter receptors. Non-CNS tissue macrophage such as lymph node macrophages and Langerhans cells in skin could also be examined for functional and morphological abnormalities in schizophrenia. Post-mortem brains from patients with schizophrenia could also be examined for microglia abnormalities. Microglia dysfunction is an integrative theory of the etiology of schizophrenia. It draws together several lines of evidence in schizophrenia including neurodevelopmental theories, early viral exposure, perinatal complications, immune system abnormalities and the negative correlation between schizophrenia and rheumatoid arthritis. It also provides a cellular basis for neurodevelopmental theories of schizophrenia. Only with ongoing study will the accuracy of this proposed theory be supported or discredited. ACKNOWLEDGEMENTS The author would like to acknowledge Janice Bacino MLS, medical librarian of St Peter’s Hospital, Helena, MT, for all her patience and diligence in assisting with this manuscript’s preparation.

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