Maternal immune activation: Implications for neuropsychiatric disorders

Abstract

Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying and developing new treatments for individuals at heightened risk for neuroimmune disorders are considered.

Figure 1. MIA as a disease primer

This schematic depicts the current model for how MIA leads to psychiatric disorders in offspring. Infection leads to release of pro-inflammatory cytokines and activation of T_H17 cells in the mother’s bloodstream(6, 19). A combination of genetic background, autoimmune status, and second hits during childhood and adolescence (including stress and drug abuse) combine with the consequences of maternal infection to increase the likelihood of offspring developing psychiatric disorders as adults(3, 6, 14, 37).

Figure 2. Mechanisms underlying the effects of MIA on brain function

Aberrations in the microbiome following MIA can lead to altered development of peripheral immunity, which in turn leads to alterations in brain development. Deficits in long-range connections between brain regions implicated in SZ and ASD, including the hippocampus (HC), prefrontal cortex (PFC), the anterior cingulate cortex (ACC), the orbitofrontal cortex (OFC) and the amygdala (AM) have been reported in MIA(3, 4, 14). Specific alterations in activity of glutamatergic neurons in the cortex caused by decreased function of dopaminergic neurons in the ventral tegmental area (VTA) and decreased GABAergic input also occurs in SZ and ASD as well as the MIA models(3, 4, 14). Changes in expression of immune molecules in the brain and even at synapses, including cytokines and MHCI molecules, alters synaptic plasticity and function, and contributes to the changes in circuitry and connectivity between brain regions that characterize these disorders(6). Finally, alterations in immune and neuronal signaling due to MIA may converge upon the mammalian target of rapamycin (mTOR) pathway, which regulates synapse formation, growth, translation, survival, and autophagy(68).

Figure 3

Timeline of major events occurring in brain, immune system, and gut development from conception to adulthood(–85).