Table 1 Inflammation in animal models of ASD and schizophrenia
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 |