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

Lorna Farrelly, Melanie Föcking, Yael Piontkewitz, Patrick Dicker, Jane English, Kieran Wynne, Mary Cannon, Gerard Cagney, David R. Cotter
2015 Developmental Neuroscience  
250 21 Word count: 4000 22 23 24 25 2 Abstract 26 BACKGROUND:Maternal infection is a risk factor for schizophrenia but the molecular 27 and cellular mechanisms are not fully known.Myelin abnormalities are amongst the 28 most robust neuropathological changes observed in schizophrenia and preliminary 29 evidence suggests that prenatal inflammation may play a role. 30 METHODS:Label-free liquid chromatography-mass spectrometry was performed on 31 the prefrontal cortex of adult rat offspring born to
more » ... t offspring born to dams that were exposed on 32 gestational day15 to the viral mimic polyinosinic:polycytidylic acid (Poly(I:C)[4 mg/kg]) 33 or saline and treated with the atypical antipsychotic drug Risperidone(0.045 mg/kg) or 34 saline in adolescence.Western blotting was employed to validate protein changes. 35 RESULTS:Over 1000 proteins were quanitifed in the prefrontal cortex with pathway 36 analyses implicating changes in core metabolic pathways, following prenatal Poly(I:C) 37 exposure.Some of these protein changes were absent in the prefrontal cortex of 38 Poly(I:C) treated offspring that subsequently received Risperidone treatment in 39 adolescence.Particularly interesting reductions in the expression of the myelin related 40 proteins, myelin basic protein isoform 3(MBP1) and rhombex29 were observed, which 41 were reversed by risperidone treatment.Validation by western blotting confirmed 42 changes in myelin basic protein isoform 3(MBP1), and mitogen activated kinase 43 1(MAPK1).Western blotting was extended to assess the MAPK signalling proteins due 44 to their roles in inflammation, namely phosphorylated mitogen activated kinase 45 1(pMAPK1) and phosphorylayed MAPK-activated protein kinase 2(pMAPKAPK2).Both 46 were upregulated by Poly(I:C) treatment and reversed by risperidone treatment. 47 CONCLUSIONS:Overall, our data suggests that maternal inflammation may 48 contribute to an increased risk for schizophrenia through mechanisms involving 49 3 metabolic function and myelin formation and that Risperidone in adolescence may 50 prevent or reverse such changes. 51 52 53 54 Exposure to prenatal infection has been linked to an increased risk of schizophrenia in 55 keeping with increasing recent evidence implicating inflammation in psychosis[1-5]. 56 However, the pathological mechanisms which confer vulnerability to the disease are 57 not known. Proteomics, the high-throughput large scale study of proteins, holds 58 potential to reveal pathological pathways at the molecular level and new insights into 59 disease mechanisms.Proteomic investigations of schizophrenia are steadily increasing 60 and are providing unique insights to unravel the complexities of this disorder[6]. The 61 expression of proteins involved in cell communication, signal transduction, cellular 62 metabolism, synaptic plasticity, cell growth and oxidation have been reported to be 63 altered in postmortem schizophrenia[6-8]. 64 The prefrontal cortex (PFC) is involved in the higher brain functions such as memory, 65 perception and cognitive processes and is therefore strongly implicated in 66 schizophrenia[9]. Using proteomic methods we have previously shown protein 67 expression changes in the PFC of schizophrenic patients relating to myelin, metabolic 68 and cytoskeletal function[7, 8, 10].Studies involving post-mortem tissue can be 69 confounded by factors such as post-mortem delay, tissue pH and drug treatment. 70 However, animal models based on known risk factors can aid considerably in 71 elucidating putative cellular and molecular pathways, test specific mechanistic 72 hypotheses and increase our insight into schizophrenia pathophysiology. 73 In recent years, an extensive body of research has validated the maternal immune 74 activation (MIA) model involving gestational exposure to infection or immune 75 stimulation as a means to simulate schizophrenia-like neuroanatomical, 76 neurochemical, behavioural and gene expression abnormalities[11-14]. The MIA 77 model is in line with the epidemiological association between prenatal infection and 78 Investigations of animal models of prenatal infection have demonstrated white matter 104 atrophy, reductions in myelin specific genes, reduced fractional anisotropy in white 105 matter and alterations in mitochondrial function and metabolism [29-32]. Inflammation 106 may influence myelin formation by causing a dysregulation of iron homeostasis which 107 is also central to this process [33, 34]. It has also been proposed that one effect of 108 atypical antipsychotics may be to enhance or normalise myelination changes in 109 schizophrenia [35, 36]. 110 Another mechanism by which inflamation may act is through activation of the MAPK 111 signalling pathway which increases the transcription of pro-inflammatory cytokines [37]. 112 Recent research has also implicated MAPK signalling in the proposed 113 antiinflammatory properties of Risperidone in a model of lipopolysaccharide induced 114 inflammation [38], and also in the growth and maintenance of myelin [39][40][41]. 115 In the current investigation we specifically hypothesized that myelin protein expression 116 changes would be induced in the PFC by prenatal Poly(I:C) and that these changes 117 could be reversed in adulthood by adolescent treatment with Risperidone. Risperidone 118 was utilised due to its preventative effect on behaviour and brain pathology following 119 prenatal Poly(I:C) exposure, and its previously described antiinflammatory 120 properties [20, 21, 38].
doi:10.1159/000368305 pmid:25592202 fatcat:33w7bxjzbjfzzfebjbzycj3yyq