Adulte Neurogenese und Schizophrenie – gibt es einen Zusammenhang?

Zusammenfassung

Nachdem vor mehr als vierzig Jahren entdeckt wurde, dass im adulten Gehirn der Ratte neue Neurone gebildet werden, ist es mittlerweile gesichert, dass zeitlebens vorwiegend im Gyrus dentatus des Hippocampus und der Subventrikulärzellschicht funktionsfähige Neurone neu entstehen. Dieser Prozess wird üblicherweise als adulte Neurogenese (aN) bezeichnet und findet in allen bislang untersuchten Säugetierspezies statt – auch im Menschen. Welche Rolle die aN spielt, ist aber bis jetzt im Wesentlichen ungeklärt. Eine Vielzahl von tierexperimentellen Studien legt eine Beteiligung der aN in der Pathogenese affektiver Erkrankungen nahe, was jedoch in letzter Zeit zunehmend kontrovers diskutiert wird. So konnte in post-mortem-Studien am Menschen keine Reduktion der Stammzellproliferation bei depressiven Erkrankungen gefunden werden, überraschenderweise wohl aber bei schizophrenen Psychosen. Eine gestörte aN bei der Schizophrenie könnte eine fehlerhafte zeitliche Einordnung neuer Gedächtnisinhalte verursachen und somit zu den kognitiven Defiziten schizophrener Patienten beitragen; möglicherweise trägt dieser Prozess auch zur Bildung von Wahninhalten bei. Eine „Neurogenese-Hypothese der Schizophrenie” wird weiterhin durch bildgebende Verfahren und Befunde am Tiermodell unterstützt. Letztere umfassen genetisch veränderte Mäuse, wie zum Beispiel Reelin- oder NPAS3-Knockoutmäuse, bei denen sowohl schizophrenie-analoge Verhaltensweisen als auch eine Reduktion der aN beschrieben sind. Weitere Hinweise finden sich in genetischen Assoziationsstudien. Mehrere Gene, die die aN beeinflussen – unter anderem auch NPAS3 – sind auch mit schizophrenen Erkrankungen assoziiert. Diese Studien, die sich vollkommen verschiedener methodischer Ansätze bedienen, legen übereinstimmend eine Störung der aN bei schizophrenen Psychosen nahe.

Summary

More than 40 years of research have convincingly demonstrated that the adult mammalian brain is capable to generate new neurons from neuronal stem cells. This process, which also occurs in humans, has been termed “adult neurogenesis” (AN) and takes place in the dentate gyrus of the hippocampus and the subventricular zone. Its function however remains elusive; as stress decreases and antidepressant treatment increases AN in animal studies, a role for AN in the pathogenesis of depression has been proposed. This nevertheless has been recently questioned, as human studies did not find lower rates of neural stem cell proliferation in affective disorders. However, decreased AN was demonstrated in schizophrenia. Given the functions of the hippocampus, disordered AN might contribute to cognitive deficits in schizophrenia, but also to the development of delusional reality perception. Neuroimaging as well as animal studies further support the notion of disturbed AN in schizophrenia, as e.g. mice deficient in reelin or NPAS3 feature behavioural abnormalities reminiscent of schizophrenia together with disturbed AN. Furthermore, human case-control studies demonstrate an association of genes, which regulate AN levels, with schizophrenia; those include BDNF, DISC1, and – again – NPAS3. Together, several lines of evidence thus argue for an involvement of AN in the pathogenesis of schizophrenia.

Schlüsselwörter

Adulte Neurogenese - Schizophrenie - Kandidatengene - neuronale Stammzellen - psychische Erkrankungen - postmortem-Studie

Keywords

Adult neurogenesis - schizophrenia - candidate genes - neural stem cells - psychiatric disorders - post mortem findings

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