Uticaj modulacije GABAa receptora koji sadrže [alfa]5 podjedinicu na promene ponašanja pacova prenatalno izloženih dejstvu lipopolisaharida

Abstract

Epidemiološke studije dovele su u vezu prenatalno izlaganje efektima imune aktivacije izazvane virusnim, bakterijskim ili parazitskim infekcijama sa povećanim rizikom od nastanka neurorazvojnih poremećaja poput shizofrenije. Ova saznanja dovela su do razvoja animalnih modela prenatalne imune aktivacije sa ciljem da se u njima modeluju simptomi i patofiziološki mehanizmi relevantni za određena neurorazvojna oboljenja. Utvrđeno je da primena lipopolisaharida (LPS), imunogene komponente ćelijskog zida gram-negativnih bakterija, gravidnim ženkama glodara izaziva febrilni odgovor i indukciju više citokina, čime utiče na balans pro- i antiinflamatornih medijatora koji je neophodan za pravilan razvoj mozga fetusa.U proučavanju etiologije shizofrenije akcenat je nedavno pomeren ka ispitivanjima poremećaja GABA-ergičkog sistema, a deficiti GABA-ergičke transmisije koji su zabeleženi kod pacijenata obolelih od shizofrenije nađeni su i u modelima prenatalne primene LPS-a gravidnim ženkama pacova. Od posebnog značaja za ispitivanja predstavljena u ovoj disertaciji stoje informacije da se vreme primene LPS-a u našem istraživanju poklapa sa periodom prvobitne ekspresije α5GABAA receptora u fetusnom mozgu pacova, kao i da prenatalna primena LPS-a u tim danima gestacije rezultira smanjenjenjem GABA-ergičke transmisije u hipokampusu potomaka u periodu preadolescencije. Otkrivanje ranih poremećaja u razvoju CNS-a leži u osnovi strategije prevencije razvoja shizofrenije i srodnih poremećaja, koja podrazumeva farmakološko delovanje na neurorazvojne promene u nastanku, pre ispoljavanja prvih simptoma.U ovoj studiji, LPS (serotip O111:B4, Escherichia coli) je primenjivan gravidnim ženkama Wistar pacova 15. i 16. dana gestacije u dozi od 100 μg/kg. Prenatalna inflamacija je detektovana kroz porast nivoa citokina TNF-α u krvi majke i placentalnom tkivu, i povećanje koncentracije IL-6 u krvi majke i amnionskoj tečnosti, dok fetusna neuroinflamacija posredovana ovim citokinima nije potvrđena. Ipak, istovremeno sa porastom koncentracije IL-6 u amnionskoj tečnosti zabeležen je porast nivoa GABA-e i smanjenje nivoa glutamata u fetusnim mozgovima...

Epidemiological studies have linked the exposure to the effects of maternal immune activation induced by viral, bacterial or parasitic infections, with the emergence of schizophrenia and several other neurodevelopmental disorders. These findings led to the development of animal models of prenatal immune activation designed to model symptoms and pathological mechanisms relevant to certain neurodevelopmental disorders. It has been shown that administration of lipopolysaccharide (LPS), an immunogen component of the cell wall of gram-negative bacteria, to pregnant rodents causes febrile response and cytokine induction, thus affecting the balance between pro- and anti-inflammatory mediators which is necessary for regular development of the fetal brain.Within the studying of etiology of schizophrenia, a focus of investigation has recently been shifted to abnormalities observed in GABA-ergic system, and deficits of GABA-ergic transmission recorded in schizophrenia patients have also been found in rats tested in models of prenatal LPS administration. Some GABA-related findings are of special interest for investigation presented in this dissertation: the time of LPS administration in our protocol is the very time of primary expression of α5GABAA receptors in rat fetal brain, and prenatal LPS administration the selected days of gestation results in a decrease of GABA-ergic transmission in the hippocampus of preadolescent offspring. The discovery of early disturbances in the development of CNS underlies the strategy for prevention of schizophrenia and related disorders, which implies a pharmacological treatment of neurodevelopmental changes at their occurrence, before the manifestation of first symptoms.In this study, LPS (serotype O111:B4, Escherichia coli) was administered to pregnant Wistar rats at 15th and 16th day of gestation, at the dose of 100 μg/kg. Prenatal inflammation was detected via the elevation of TNF-α concentration in maternal blood and placenta, and IL-6 concentration in maternal blood and amniotic fluid, while fetal neuroinflammation mediated with these cytokines was not confirmed...