Die Rolle der Homer1a-vermittelten Regulation glutamaterger Neurotransmission bei der antidepressiven Behandlung
Experimentelle Modelle zum Verständnis von Erkrankungen des Nervensystems
Kognitive, systemische und Verhaltensneurobiologie
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Major depressive disorder is the most common mental diseases. The widely used monoaminebased antidepressant drugs require weeks to month to improve symptoms, have low response rates and often cause side effects. Therefore, the search for mechanistically novel and more effective therapeutic options for depression is currently a research priority. We have previously identified that the induction of the synaptic plasticity protein Homer1a specifically in the medial prefrontal cortex (mPFC) is an important element for the antidepressant therapy. Moreover, our work has shown that the restoration of synaptic plasticity in hippocampus represents a key factor in the antidepressant response. The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view that links these processes remains elusive. In the current funding period, using a combination of circuit manipulation, electrophysiological recordings, in vivo fiber photometry and behavior analyses, we identify a convergent circuit for antidepressant response and plasticity modulation that links mPFC and hippocampus. We demonstrated that chemogenetic activation (utilizing designer receptor exclusively activated by designer drugs) of the mPFC excitatory neurons is sufficient to exert rapid antidepressant effects across multiple behavioral domains in a mouse model of stress-induced depression and exerts top-down control over hippocampal plasticity and processing, as mPFC stimulation enhances structural plasticity, restores long-term potentiation and improves state-dependent network dynamics in the hippocampus. Furthermore, we identified the nucleus reuniens (RE) as a necessary mediator of these effects. Notably, RE inhibition blocks not only mPFC-stimulation-induced antidepressant response, but also the therapeutic and neuroplastic effects of ketamine. Our findings demonstrate that the functional mPFC → RE → hippocampus circuit plays a central role in the antidepressant response, linking circuit activity, hippocampal plasticity, and depressive-like behaviors. Taken together our data contribute in the long-run, by better characterization of the molecular, cellular and circuitry mechanisms of the rapid antidepressant response, to the generation of more selective and efficacious treatment approached for depression.
Projektbezogene Publikationen (Auswahl)
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d-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity. Translational Psychiatry, 14(1).
Vestring, Stefan; Dorner, Alexandra; Scholliers, Jonas; Ehrenberger, Konstantin; Kiss, Andrea; Arenz, Luis; Theiss, Alice; Rossner, Paul; Frase, Sibylle; Du Vinage, Catherine; Wendler, Elisabeth; Serchov, Tsvetan; Domschke, Katharina; Bischofberger, Josef & Normann, Claus
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Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice. Nature Communications, 15(1).
Sarrazin, David H.; Gardner, Wilf; Marchese, Carole; Balzinger, Martin; Ramanathan, Chockalingam; Schott, Marion; Rozov, Stanislav; Veleanu, Maxime; Vestring, Stefan; Normann, Claus; Rantamäki, Tomi; Antoine, Benedicte; Barrot, Michel; Challet, Etienne; Bourgin, Patrice & Serchov, Tsvetan
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The NMDA receptor subunit GluN2D is a target for rapid antidepressant action. Springer Science and Business Media LLC.
Normann, Claus; Vestring, Stefan; Veleanu, Maxime; Perez, Marina Conde; Bronnec, Martin; Li, Anna; Würz, Lovis; Erdogdu, Fatih; Stocker, Julia; Moos, Johanna; Weigel, David; Theiß, Alice; Wendler, Elisabeth; Borger, Lotta; Voita, Sabine; Heynicke, Franziska; Brandl, Jakob; Hummel, Fabian; Vivet, Clotilde ... & Bischofberger, Josef
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Linking Brain Circuitry and Neural Plasticity in Antidepressant Response: The mPFC-Reuniens-Hippocampus Pathway.. Springer Science and Business Media LLC.
Vestring, Stefan; Veleanu, Maxime; Weber, Jakob; Schwär, Tim; Schuberth, Louise; Sarrazin, David; Anselin, Marguerite; Rutke, Lukas; Suarez-Marchi, Guillermo Jose; Zimmermann, Stella; Borgeest, Zoe; Balzinger, Martin; Blendinger, Alina; Catarata, Anna; Dib, Samira Assaad; Cholvin, Thibault; Sych, Yaroslav; Domschke, Katharina; Normann, Claus & Serchov, Tsvetan
