The RNA topoisomerase Top3b is required for normal synapse structure and function in mice

FARE Award Winner

Authors

• W Peng
• Y Wang
• J Sima
• W Shen
• M Mattson
• W Wang

Abstract

Top3b is the first RNA topoisomerase identified in eukaryotes. It biochemically and genetically interacts with FMRP, a protein that is deficient in fragile X syndrome (FXS). 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 risks to develop schizophrenia and intellectual disability. Here we show that Top3b-deficient mice have abnormal synapse formation, a phenotype similar to FMRP-knockout mice. Specifically, cultured primary neurons from Top3b mutant mice exhibit decreased synaptic vesicles and synapses represented by reduced immunostaining of the presynaptic and postsynaptic markers, synaptophysin and PDS95. Notably, 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. Moreover, an mGluR5 antagonist can largely rescue the abnormal LTP evoked by synaptic stimulation in hippocampus of Top3b-knockout mice. This resembles previous findings that the same type of antagonists can largely rescue the abnormal synaptic transmission in FMRP-deficient mice. Mechanistically, Top3b binds to a group of synaptic mRNAs, which are crucial for synaptogenesis and synaptic activation, and may regulate their stability and translation.These findings indicate that Top3b plays an important role in regulating synaptic formation and activity-dependent synaptic plasticity in the brain. Moreover, the data also raise a possibility that mGluR antigonists may be used to treat not only patients with Fragile X syndrome, but also those with schizophrenia and intellectual disability caused by Top3b mutations.

Scientific Focus Area: Molecular Biology and Biochemistry

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