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<p>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.</p>

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A molecular mechanism mediating clozapine-enhanced sensorimotor gating

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月11日

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

摘要

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.