Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Abstract

The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course. Molecular Psychiatry (2001) 6, 634-646.

Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

“…This in turn supports the hypothesis that immune activation during pregnancy may in part be responsible for the interaction between maternal infection during pregnancy and schizophrenia Kirch, 1993;Nawa et al, 2000;Pearce, 2001;Wright et al, 1993). Moreover, prenatal poly I : C administration may provide a unique model in terms of the study of induction at the functional level, because immune activation precisely timed to specific periods of fetal neurodevelopment may allow the characterization of critical risk periods during which immuneinduced disruption of selectively vulnerable neuronal populations/systems can lead to dysfunctional brain circuitries and postpubertal pathology relevant to schizophrenia.…”

“…The potential role of cytokines is underscored by findings that prenatal exposure to a variety of infections has been associated with an increased incidence of schizophrenia (O'Callaghan et al, 1994;Torrey et al, 1982Torrey et al, , 1988Watson et al, 1984;Yolken et al, 2000), indicating that such an association may be mediated by a host response that is common to all infections Marx et al, 2001;Nawa et al, 2000;Pearce, 2001). …”

“…The mechanisms whereby viral insults during neuroontogenesis can cause latent pathology in the CNS remain unknown, but it has been suggested that the maternal immune response, and in particular, proinflammatory cytokines released by the maternal immune system, may interfere with normal fetal brain development Kirch, 1993;Marx et al, 2001;Nawa et al, 2000;Pearce, 2000Pearce, , 2001Waltrip et al, 1990;Wright et al, 1993). The potential role of cytokines is underscored by findings that prenatal exposure to a variety of infections has been associated with an increased incidence of schizophrenia (O'Callaghan et al, 1994;Torrey et al, 1982Torrey et al, , 1988Watson et al, 1984;Yolken et al, 2000), indicating that such an association may be mediated by a host response that is common to all infections Marx et al, 2001;Nawa et al, 2000;Pearce, 2001).…”

Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10

“…30,31 Prenatal, neonatal and adult infections leading to development of schizophrenia were repeatedly investigated, including viral, retroviral and bacterial pathogens. [1][2][3]5,6,[32][33][34] Several mechanisms of Chlamydophila infection may disturb brain function. Interestingly, the bloodbrain barrier seems to be disturbed in some stages of schizophrenia.…”

Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice

“…A number of working hypotheses propose that viral infection, as an environmental factor, contributes to the induction of neuropathological and neurophysiological disturbances, resulting in a wide range of behavioral abnormalities (1)(2)(3). Studies using animal models reveal that viruses can induce neurobehavioral disturbances predominantly through an indirect pathway that involves the release of various factors by infiltrating cells or by glial cells (3)(4)(5).…”