AbstractHPC‐1/syntaxin 1A (STX1A) is thought to regulate the exocytosis of synaptic vesicles in neurons. In recent human genetic studies,STX1Ahas been implicated in neuropsychological disorders. To examine whetherSTX1Agene ablation is responsible for abnormal neuropsychological profiles observed in human psychiatric patients, we analysed the behavioral phenotype ofSTX1Aknockout mice. Abnormal behavior was observed in both homozygotes (STX1A−/−) and heterozygotes (STX1A+/−) in a social interaction test, a novel object exploring test and a latent inhibition (LI) test, but not in a pre‐pulse inhibition test. Interestingly, attenuation of LI, which is closely related to human schizotypic symptoms, was restored by administration of the selective serotonin reuptake inhibitor, fluoxetine, but not by the dopamine reuptake inhibitor, GBR12935, or the noradrenalin reuptake inhibitor, desipramine. We also observed that LI attenuation was restored by DOI (a 5‐HT2Areceptor agonist), but not by 8‐OH‐DPAT (a 5‐HT1Areceptor agonist), mCPP (a 5‐HT2Creceptor agonist), SKF 38393 (a D1receptor agonist), quinpirole (a D2/D3receptor agonist) or haloperidol (a D2/D3receptor antagonist). Thus, attenuation of LI is mainly caused by disruption of 5‐HT‐ergic systems via 5‐HT2Areceptors. In addition, 5‐HT release from hippocampal and hypothalamic slices was significantly reduced. Therefore, ablation ofSTX1Amay cause disruption of 5‐HT‐ergic transmission and induce abnormal behavior.