A molecular mechanism mediating clozapine-enhanced sensorimotor gating

Ioannis Mantas; Ivana Flais; Niclas Branzell; Tudor M Ionescu; Eugene Kim; Xiaoqun Zhang; Diana Cash; Bastian Hengerer; Per Svenningsson

doi:10.1038/s41386-025-02060-z

A molecular mechanism mediating clozapine-enhanced sensorimotor gating

Ioannis Mantas, Ivana Flais, Niclas Branzell, Tudor M Ionescu, Eugene Kim, Xiaoqun Zhang, Diana Cash, Bastian Hengerer, Per Svenningsson

Research output: Contribution to journal › Article › peer-review

Abstract

The atypical antipsychotic clozapine targets multiple receptor systems beyond the dopaminergic pathway and influences prepulse inhibition (PPI), a critical translational measure of sensorimotor gating. Since PPI is modulated by atypical antipsychotics such as risperidone and clozapine, we hypothesized that p11-an adaptor protein associated with anxiety- and depressive-like behaviors and G-protein-coupled receptor function-might modulate these effects. In this study, we assessed the role of p11 in clozapine's PPI-enhancing effect by testing wild-type and global p11 knockout (KO) mice in response to haloperidol, risperidone, and clozapine. We also performed structural and functional brain imaging. Contrary to our expectation that anxiety-like p11-KO mice would exhibit an augmented startle response and heightened sensitivity to clozapine, PPI tests showed that p11-KO mice were unresponsive to the PPI-enhancing effects of risperidone and clozapine. Imaging revealed distinct regional brain volume differences and reduced hippocampal connectivity in p11-KO mice, with significantly blunted clozapine-induced connectivity changes in the CA1 region. Our findings highlight a novel role for p11 in modulating clozapine's effects on sensorimotor gating and hippocampal connectivity, offering new insight into its functional pathways.

Original language	English
Article number	107829
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Early online date	11 Feb 2025
DOIs	https://doi.org/10.1038/s41386-025-02060-z
Publication status	E-pub ahead of print - 11 Feb 2025

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Mantas, I., Flais, I., Branzell, N., Ionescu, T. M., Kim, E., Zhang, X., Cash, D., Hengerer, B., & Svenningsson, P. (2025). A molecular mechanism mediating clozapine-enhanced sensorimotor gating. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Article 107829. Advance online publication. https://doi.org/10.1038/s41386-025-02060-z

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A molecular mechanism mediating clozapine-enhanced sensorimotor gating

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