Maternal Immune Activation Induces Changes in Myelin and Metabolic Proteins, Some of Which Can Be Prevented with Risperidone in Adolescence

Abstract

Background: Maternal infection is a risk factor for schizophrenia but the molecular and cellular mechanisms are not fully known. Myelin abnormalities are amongst the most robust neuropathological changes observed in schizophrenia, and preliminary evidence suggests that prenatal inflammation may play a role. Methods: Label-free liquid chromatography-mass spectrometry was performed on the prefrontal cortex (PFC) of adult rat offspring born to dams that were exposed on gestational day 15 to the viral mimic polyinosinic:polycytidylic acid [poly(I:C), 4 mg/kg] or saline and treated with the atypical antipsychotic drug risperidone (0.045 mg/kg) or saline in adolescence. Western blotting was employed to validate protein changes. Results: Over 1,000 proteins were quantified in the PFC with pathway analyses implicating changes in core metabolic pathways, following prenatal poly(I:C) exposure. Some of these protein changes were absent in the PFC of poly(I:C)-treated offspring that subsequently received risperidone treatment in adolescence. Particularly interesting reductions in the expression of the myelin-related proteins myelin basic protein isoform 3 (MBP1) and rhombex 29 were observed, which were reversed by risperidone treatment. Validation by Western blotting confirmed changes in MBP1 and mitogen-activated kinase 1 (MAPK1). Western blotting was extended to assess the MAPK signalling proteins due to their roles in inflammation, namely phosphorylated MAPK1 and phosphorylated MAPK-activated protein kinase 2. Both were upregulated by poly(I:C) treatment and reversed by risperidone treatment. Conclusions: Overall, our data suggest that maternal inflammation may contribute to an increased risk for schizophrenia through mechanisms involving metabolic function and myelin formation and that risperidone in adolescence may prevent or reverse such changes.

Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders

“…Moreover, alterations in white matter, such as volume reductions in prefrontal areas and increased density in subcortical areas, morphologic abnormalities in oligodendroglia and myelin-related gene abnormalities have all been related to schizophrenia (Sanfilipo 2000a(Sanfilipo , 2000bConnor et al 2011). Our findings here, together with those reported by Fatemi et al and Farrelly et al (Fatemi et al 2005, 2009a, 2009bFarrelly et al 2015), highlight that the pathological relationship between prenatal infection and neurodevelopmental psychiatric disorders involves the disruption of myelination-related processes.…”

“…The consistency between our findings and those reported by Fatemi and colleagues thus suggests that reduced expression of markers of myelin stability and functionality could be a long-lasting molecular signature of various prenatal immune challenges. Additional support for this hypothesis also stems from recent proteomic analyses demonstrating similar effects of prenatal viral-like immune activation on myelination-related proteins (Farrelly et al 2015). Indeed, Farrelly et al (2015) also uncovered changes in myelinrelated proteins, such as MBP1 and rhombex 29, suggesting that prenatal infection may contribute to neurodevelopmental abnormalities through mechanisms involving myelin formation and functionality (Farrelly et al 2015).…”

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

“…as these gene-environment interactions may play a role in SZ pathophysiology, disease onset, or penetrance. Maternal immune activation, for example, has been shown to alter mitochondrial proteins involved in core metabolic pathways, and may be one mechanism by which genetic susceptibility and environmental stressors collectively contribute to SZ [99]. …”

Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study

“…Prior studies provide evidence that disruption of neurogenesis, vascular integrity, metabolic abnormalities and altered excitation – inhibition balance may be linked to hippocampus and or prefrontal cortex volume loss in following MIA (Hadar et al, 2015, Patrich et al, 2016, Piontkewitz et al, 2012b, Vernon et al, 2015, Meyer et al, 2008, Nyffeler et al, 2006, Richetto et al, 2014). More recently combining MRI and genome-wide transcription or proteomics analysis suggests MIA induces myelin dysfunction, which will be important to explore in terms of our observations of increased white matter volume (Farrelly et al, 2015, Richetto et al, 2016). There is also evidence for decreased levels of in synaptic proteins in the hippocampus and PFC of POL-exposed mice (Giovanoli et al, 2015, Giovanoli et al, 2016), whilst evidence for microglial activation is equivocal (Giovanoli et al, 2015, Giovanoli et al, 2016; Mattei et al, 2014, Eßlinger et al, 2016).…”