Characterization of a rat model of Maternal Immune Activation with relevance to schizophrenia

Stephan Missault
Je bent zwanger en krijgt de griep: vergroot dit werkelijk de kans op schizofrenie bij je kind?Een studie van de hersenen en het gedrag van de rat…Tijdens mijn masterproef werden zwangere ratten ingespoten met een virale nabootser, die een immuunrespons opwekt in het lichaam alsof je de griep zou hebben. De immuun-eiwitten die worden opgewekt in het lichaam van de moeder circuleren in het bloed en kunnen via de placenta de foetussen bereiken.

Characterization of a rat model of Maternal Immune Activation with relevance to schizophrenia

Je bent zwanger en krijgt de griep: vergroot dit werkelijk de kans op schizofrenie bij je kind?

Een studie van de hersenen en het gedrag van de rat…

Tijdens mijn masterproef werden zwangere ratten ingespoten met een virale nabootser, die een immuunrespons opwekt in het lichaam alsof je de griep zou hebben. De immuun-eiwitten die worden opgewekt in het lichaam van de moeder circuleren in het bloed en kunnen via de placenta de foetussen bereiken. Men gelooft dat deze immuun-eiwitten veranderingen teweeg brengen in de ontwikkeling van de hersenen van de foetussen en zo de kans vergroten dat deze nakomelingen schizofreen worden tijdens het jongvolwassen leven. Eén theorie is dat dit gebeurt door activatie van microglia, de belangrijkste immuuncellen in de hersenen, die mogelijk geactiveerd blijven tot in het volwassen leven. In een eerste studie werd de meest optimale dosis van de virale nabootser bepaald alsook de fase van de zwangerschap waarbij injectie met de virale nabootser het grootste effect heeft op de immuunrespons in de moeders en foetussen. In de tweede studie werden zwangere ratten geïnjecteerd met de beste dosis van de virale nabootser tijdens de late zwangerschap. Vervolgens werd er gekeken of de moeders gewicht verloren of bijkwamen na injectie met deze virale nabootser. Eens de mannelijke nakomelingen volwassen waren, ondergingen ze verschillende gedragstesten om te onderzoeken of ze schizofreen waren. De nakomelingen van de moeders die gewicht verloren na injectie met de virale nabootser hadden verschillende gedragsafwijkingen die doen denken aan schizofrenie. De nakomelingen van de moeders die geen gewicht verloren, hadden veel minder gedragsafwijkingen. Na de gedragstesten werden de nakomelingen opgeofferd en de hersenen uit de schedels gehaald. Ten slotte werd er gekeken of de microglia geactiveerd waren in de hersenen van de “schizofrene” ratten. We ontdekten voor de eerste keer dat er veel meer microglia geactiveerd waren in de hersenen van de nakomelingen van moeders die gewicht verloren na inspuiting met de virale nabootser dan in de hersenen van de nakomelingen van moeders die geen gewicht verloren. De nakomelingen van moeders die gewicht verloren na inspuiting vertoonden dus niet alleen veel abnormaler gedrag dan de nakomelingen van moeders die geen gewicht verloren, maar hadden ook meer geactiveerde immuuncellen in hun hersenen. Hierdoor kunnen we nu als hypothese stellen dat er een directe link is tussen de activatie van microglia in de hersenen en het “schizofreen” gedrag in deze dieren.

Zoals eerder vermeld werden zwangere ratten in de eerste studie geïnjecteerd met verschillende dosissen van de virale nabootser: een lage, gemiddelde en hoge dosis. Ongeveer de helft van de ratten werd geïnjecteerd iets voor de helft van de zwangerschap. De andere helft werd ingespoten tijdens de late zwangerschap. Andere ratten werden ingespoten met water en dienden als referentie. Zes uur na de injectie werden de ratten opgeofferd. Er werd een bloedstaal genomen van de moeders en er werden een aantal foetussen gedissecteerd uit de baarmoeder van de rat. Vervolgens werden de hersenen van de foetus gedissecteerd en bijgehouden. Tot slot hebben we indirect de hoeveelheid immuun-eiwitten gemeten in het bloed van de moeders en de hersenen van de foetussen. Tot onze verbazing waren de immuun-eiwitten meestal het sterkst gestegen na een injectie met de gemiddelde dosis van de virale nabootser en niet na de hoogste dosis. De meest interessante resultaten werden bekomen bij een injectie tijdens de late zwangerschap.

In de tweede studie werden ratten daarom geïnjecteerd met de gemiddelde dosis van de virale nabootser tijdens de late zwangerschap. Er werden opnieuw ratten ingespoten met water als referentie. Vervolgens werd er opgevolgd welke ratten gewicht verloren na injectie en welke gewicht bijkwamen. Eens de mannelijke nakomelingen volwassen waren, werden ze onderworpen aan drie gedragstesten. De eerste test onderzocht of de ratten problemen hadden om overbodige informatie uit hun omgeving weg te filteren. Schizofrene patiënten kampen immers met het probleem dat ze belangrijke en onbelangrijke informatie niet meer kunnen onderscheiden. Alles lijkt belangrijk voor hen. Tijdens de tweede test werd er gekeken naar de activiteit van de ratten in hun kooi: zitten ze lang stil of lopen ze veel rond? Zowel spontane activiteit werd onderzocht als de activiteit uitgelokt door toediening van bepaalde drugs: amfetamine en MK-801 (vergelijkbaar met een drug als ‘angel dust’). Deze drugs kunnen bij gezonde mensen een acute psychose veroorzaken. Schizofrene patiënten zijn vaak gevoeliger voor deze drugs. Bij ratten veroorzaken ze in lage dosis hyperactiviteit, maar net als bij patiënten gaan “schizofrene” ratten anders reageren op deze drugs dan gezonde ratten. Tot slot werd in een laatste test onderzocht of de ratten problemen hadden om plezier te beleven, een symptoom die ook bij schizofrenen voorkomt. De nakomelingen van moeders die gewicht verloren na de immuun-activatie vertoonden in vrijwel elke test abnormaal gedrag. De nakomelingen van moeders die geen gewicht verloren, vertoonden vaker normaal gedrag. Ze waren echter ook niet geheel vrij van abnormaliteiten vergeleken met de nakomelingen van de moeders die met water werden ingespoten. Als we uiteindelijk gingen kijken naar de activiteit van de belangrijkste immuuncellen in de hersenen, de microglia, dan ontdekten we dat de ratten met het meest abnormale gedrag ook de grootste microglia-activatie hadden. Dit suggereert een belangrijk verband tussen de activiteit van de microglia en het “schizofreen” gedrag in deze ratten.

We kunnen concluderen dat een antivirale immuunrespons tijdens de zwangerschap een belangrijke risicofactor is voor schizofrenie bij de nakomelingen. Er hangt echter veel af van de manier waarop de moeder reageert op het virus (of de virale nabootser). Aan de andere kant zijn de geobserveerde gedragsafwijkingen eerder subtiel. De oorzaak van schizofrenie is waarschijnlijk ook niet eenzijdig. Verschillende risicofactoren, zowel overgeërfde als andere, werken vermoedelijk samen om schizofrenie bij de mens te veroorzaken. Desalniettemin kan het interessant zijn om zich vóór de zwagerschap te laten inenten tegen het influenza-virus, het voornaamste virus dat de griep veroorzaakt. De kleine immuun-activatie die een vaccin veroorzaakt zou immers risicovol kunnen zijn als men reeds zwanger is. Meer onderzoek is hiervoor echter nodig.

Het is ook belangrijk te beseffen dat de activatie van microglia in de hersenen een belangrijke rol kan spelen bij schizofrenie en dat therapieën gericht op deze immuuncellen hulp kunnen bieden bij het bestrijden van deze belangrijke ziekte.

Bibliografie

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Universiteit of Hogeschool
Biomedische wetenschappen: neurosciences
Publicatiejaar
2013
Kernwoorden
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