A molecular mechanism mediating clozapine-enhanced sensorimotor gating

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.