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Table 1 Inflammation in animal models of ASD and schizophrenia

From: Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations

Disease Animal model Trigger Main features and outcomes Inflammatory molecules, cells and processes References
Genetic models
ASD BTBR mice Crossing of inbred strain at (non-agouti; black and tan) and wild-type T (brachyury) mutations, with mice carrying tufted (Itpr3tf) allele Avoid social interaction; increased repetitive behaviors; altered functional connectivity;
loss of corpus callosum; formation of the cortical area and interhemispheric connectivity altered in an age- and region-specific manner; altered oxidative stress mechanisms
Higher brain-reactive IgG levels; increased microglia activation; increased pro-inflammatory cytokines (IL-1b, IL-18 and IL-33, IL-6, IL-12); decreased B cells; increased numbers of CD4 T cells; enhanced M1 macrophage polarization Careaga et al. 2015; Fenlon et al. 2015; Heo et al. 2011; Hwang et al. 2015; Kim et al. 2016; Meyza et al. 2013; Onore et al. 2013; Sforazzini et al. 2014; Shpyleva, Ivanovsky, 2014
ASD/Rett syndrome Mecp2 mutant mice and non-human primates Mecp2 gene mutation or duplication Model of Rett syndrome. Repetitive locomotion, increased anxiety, reduced social interaction, and relatively weak cognitive phenotypes Activation, followed by loss of microglia and some monocytes and macrophage populations (e.g., meningeal) Cronk et al. 2015; Liu et al. 2016
Schizophrenia DISC1 mutant mice DISC1 gene mutation Alteration in brain connectivity and function during development; behavioral and cognitive impairments;
anatomical, cell biological, and circuitry deficits
Impaired GSK-3b signaling; higher IL-1b and IL-5 in fetal brain Flores, Morales-Medina, 2016; Tomoda et al. 2016; Abazyan et al. 2010
Neurodevelopmental models
ASD Pre-natal stress/exposure models e.g., administration of VPA during pregnancy Decreased social interaction in adult males; reduced cognitive function Increased basal glial activation; altered systemic inflammation; changes in immunity-related gene expression; increased intestinal inflammation Lucchina and Depino, 2014; Huang et al. 2016; de Theije et al. 2014; Hill, 2015
ASD and schizophrenia Maternal immune activation (MIA) in mice or primates Maternal infection or immune stimulation (LPS, PolyI:C,) Reduced PPI and ultrasonic vocalizations; decreased sociability and increased repetitive or stereotyped behavior; involvement of parvalbumin expressing interneurons in medial pre-frontal cortex; neurochemical and brain morphological abnormalities (enlarged ventricles; spatially localized deficit in Purkinje cells); decreased neurogenesis; impaired synaptic development Maternal cytokine upregulation (IL-1β, IL-6, TNF-α IL-17, IL-10); fetal and neonatal increased cytokine levels in areas of the brain (frontal and cingulated cortex, and hippocampus) and in serum; increased cytokine and chemokine expression in the fetal brain; controversy on increased levels of microglial activation Choi et al., 2016; Canetta et al. 2016; Garay, Hsiao, 2013; Smith et al. 2007; Juckel et al. 2011, Mattei et al. 2014, Van den Eynde et al. 2014; Pratt, Ni, 2013; (Giovanoli et al. 2015, Missault, Van den Eynde, 2014, Smolders et al. 2015; Coiro et al. 2015; Machado et al. 2015)
Schizophrenia Neonatal ventral hippocampal lesion Microinjection of Ibotenic acid in the ventral hippocampus at postnatal day 7 Abnormal behavioral phenotypes after puberty;
Persistent astrogliosis and microglial activation; increase in metabotropic glutamate receptor type 5 (mGluR5); hippocampal neuronal loss
Persistent astrogliosis and microglial activation; Increased production of inflammatory mediators; Increased mGluR5 expression in astrocytes and microglia Drouin-Ouellet et al. 2011; Hill, 2015
Combination models
Schizophrenia Combination of genetic and environmental factors (G × E) MIA in the DISC1 mutant models Developmental stage-specific deficits in social behavior, spatial working memory, and PPI; decreased volume of amygdala, hypothalamus, and periaqueductal gray matter; decreased 5-HT metabolism Higher IL-6 in response to polyI:C in fetal brain in DiSC1 mutant mice; high IL-1β, reduced GSK-3β signaling and IL-5 in response to PolyI:C Abazyan et al. 2010, Meyer, 2014; O’Leary, Desbonnet, 2014; Lipina et al. 2013
ASD and schizophrenia Combination of 2 environmental factors (E × E) MIA model combined with other post-natal stressors, like being reared by stressed mother, or pubertal stress exposure Impaired working and spatial memory from pre-natal, but not postnatal maternal influence;
combination of MIA with peri-pubertal stress led to neuropathological effects in the hippocampus GABAergic cell population
Transient neuroinflammation Giovanoli, Weber, 2014; Richetto, Calabrese, 2013; Meyer, 2014