Priming of Metabolic Dysfunctions by Prenatal Immune Activation in Mice: Relevance to Schizophrenia

Abstract

Schizophrenia is associated with increased risk for multiple metabolic abnormalities, including altered glucose homeostasis, type-2 diabetes, obesity, and cardiovascular disease. Some of the metabolic alterations can already exist in psychosis-prone subjects prior to the onset of chronic schizophrenic disease and pharmacotherapy, indicating that they may have a developmental origin. In the present study, we tested the hypothesis that metabolic alterations pertinent to schizophrenic disease can be primed by an environmental risk factor associated with the disorder, namely prenatal exposure to immune challenge. We used a well-established mouse model of prenatal immune challenge induced by maternal gestational treatment with poly(I:C) (="polyriboinosinic-polyribocytidilic acid"), an analog of double-stranded RNA that stimulates a cytokine-associated viral-like acute phase response. Metabolic effects were studied using high-resolution computed tomography and fully automated indirect calorimetry system, along with an oral glucose tolerance test and plasma cytokine and corticosterone measurements. We found that prenatal immune activation caused altered glycemic regulation and abnormal ingestive behavior in periadolescence and led to an adult onset of excess visceral and subcutaneous fat deposition. These effects were accompanied by age-dependent changes in peripheral secretion of proinflammatory (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and T cell-related (IL-2 and interferon [IFN]-γ) cytokines and by increased release of the stress hormone corticosterone in periadolescence. Our findings show that schizophrenia-relevant metabolic and physiological abnormalities can be primed by prenatal viral-like immune activation, but at the same time, our study emphasizes that this environmental insult is unlikely to precipitate the full spectrum of metabolic and immunological changes pertinent to chronic schizophrenic disease.

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…The adult emergence of poly(I:C)--induced PPI deficit is consistent with numerous previous studies in mice (e.g., Lipina et al, 2013;Pacheco--López et al, 2013;Vuillermot et al, 2010) and rats ; but see also Wolff and Bilkey, 2010). Since the hippocampal formation is one of several neuronal substrates modulating sensorimotor gating (Bast and Feldon, 2003), deficient hippocampal expression of presynaptic proteins may readily contribute to the attenuation of PPI in immune--challenged offspring.…”

Long-term pathological consequences of prenatal infection: beyond brain disorders

“…Moreover, long-term metabolic abnormalities have also been observed in mouse offspring of mothers that were exposed to the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C), a synthetic analog of double-stranded RNA that induces a virus-like acute phase response (93). In this virus-like immune activation model, offspring of polyI:C-treated mouse dams were shown to develop altered glycemic regulation and abnormal ingestive behavior in adolescence and excess fat deposition in adulthood (115). Similar results were obtained in a mouse model, in which pregnant mice were infected with Ljungan virus (LV), a virus that belongs to the Picornavirus family and is virulent for laboratory rodents (126).…”

“…Some studies using rodent models of bacterial or viral maternal immune challenge have reported a significant upregulation of circulating inflammatory factors such as proinflammatory cytokines or chemokines in the juvenile or adult offspring (17,43,69). Other studies using the same animal models, however, failed to find clear signs of systemic inflammation in juvenile or adult offspring born to immunologically challenged mothers (96,157), or they even reported opposite effects that were characterized by blunted systemic inflammatory activity following prenatal infection (115).…”

“…Given that maternal immune activation alters hypothalamic functions in rodent offspring (42,78,158), neurodevelopmentally acquired abnormalities in the hypothalamus may contribute to the emergence of a hyperphagic phenotype in offspring with prenatal infection (111,115). An alternative (but not mutually exclusive) mechanism underlying such changes in food intake may be related to changes in the mesocorticolimbic dopamine system.…”

“…Initial evidence suggests that prenatal immune activation can cause hyperactivity of the sympathetic nervous system, perhaps at the expense of diminished parasympathetic nervous system functions. Hyperactivity of the sympathetic nervous system typically leads to increased secretion of noradrenaline and corticosterone, both of which have been observed in mouse offspring that were exposed to prenatal immune challenge (115,158). Prolonged secretion of these stressrelated factors can negatively influence GI physiology, including gut motility, secretion, permeability, and composition of the gut microbiota (13,67).…”