Topoisomerase 3b (TOP3B), the first RNA topoisomerase, interacts with FMR1 (FMRP), the disease gene product in fragile X mental retardation syndrome. Increasing evidence suggests that TOP3B regulates RNA metabolism and promotes synapse formation. A recent study also shows that individuals carrying deletion of TOP3B gene are at increased risk of developing schizophrenia and intellectual disability. However, the functional role and pathologic mechanism of TOP3B in mental disorders are unclear. Here we show that Top3b-deficient mice have increased anxiety and intensified fear conditioned memory compared with wild type mice in several behavioral tests. In addition,Top3b-deficient mice display enlarged ventricles, a phenotype commonly observed in schizophrenia patients. These enlarged ventricles could be due to reduced proliferation and differentiation of adult neural stem cells in subventricular zone (SVZ) and hippocampus of Top3b-deficient mice. Furthermore, we show that two forms of protein synthesis-dependent synaptic plasticity, long-term depression (LTD) and long-term potentiation (LTP) that involve activation of metabotropic glutamate receptors (mGluRs), are impaired in the hippocampus of Top3b-deficient mice. Mechanistically, TOP3B binds to a group of mRNAs, which are crucial for adult neurogenesis and newly developed tissue structure; and may regulate an emotional condition including anxiety level and fear memory. Our data demonstrate that TOP3B is required for adult neural genesis and synaptic plasticity, and provides a mechanism for how its mutation can lead to neurodevelopmental disorders. .