Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology

Abstract

Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.

Fetal programming of neuropsychiatric disorders

“…The proposed mechanism involves the activation of the cytokine pathway during pregnancy: it can affect the metabolism of tryptophan leading to an excess in serotonin production potentially harmful for the development of the brain (Kubesova et al, ), that is coherent with the serotoninergic hypothesis of autistic spectrum disorders and SCZ (Croen et al, ; Miller, Llenos, et al, ; Quaak et al, ).…”

“…Evidence coming from animal studies allowed the investigators to hypothesize a link between maternal immune activation in pregnancy and neuropsychiatric disorders in the offspring (Enayati et al, ). In particular, offsprings from dams chronically treated with Lipo‐Poli‐Saccharide coming from E. coli during pregnancy showed antisocial, psychotic, and autistic symptomatology (Kubesova et al, ). It seems that this correlation may be valid also in human, given the recent epidemiological studies that show a correlation between several infective diseases and autism (Vargas et al, ).…”

Effects of early life stress on biochemical indicators of the dopaminergic system: a 3 level meta-analysis of rodent studies

“…Zhang et al 2013), striatal DR2(Y. Zhang et al 2015), DAT in the VTA area(Tien et al 2013), striatal DOPAC(Ognibene et al 2008), cortical DA(Matthews et al 2001) and limbic HVA(Kubesova et al 2015)) were excluded from the analysis as outliers.…”

“…Hensleigh and Pritchard 2014; Hermel et al 2001; Hill et al 2014; J. W. Jahng et al 2010; Jeong Won Jahng et al 2012; Katunar et al 2010; Kawakami et al 2013; Kikusui, Faccidomo, and Miczek 2005; Kirsten et al 2012; Kubesova et al 2015; Lazzaretti et al 2015; Lejeune et al 2013; Li et al 2014; Z. D. Ling et al 2004; Z.…”

Stimulatory effect of repeated treatment with lipopolysaccharide on a key enzyme of the kynurenine pathway in both genders in rats

“…Repeated administration of LPS can be used as a model of chronic stress and also as a model for immune system activation. Among others, the administration of LPS leads to activation of the kynurenine pathway of tryptophan metabolism (Kubesova et al 2015). The kynurenine pathway consists of two functionally distinct branches that generate several neuroactive metabolites.…”