Hippocampal circAnk3 Deficiency Causes Anxiety-like Behaviors and Social Deficits by Regulating the miR-7080-3p/IQGAP1 Pathway in Mice

Abstract

Background

Circular RNAs (circRNAs) are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs (miRNAs). CircAnk3 is derived from the 11^th intron of the Ankyrin 3 (Ank3) gene, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice.

Methods

The DNA sequence from which circAnk3 is generated was modified using CRISPR/Cas9 technology, and neurobehavioral tests (anxiety and depression-like behaviours, social behaviours) were performed in circAnk3^+/- mice. A series of molecular and biochemical assays were used to investigate the function of circAnk3 as a microRNA sponge and its downstream regulatory network for target genes.

Results

CircAnk3^+/- mice exhibited both anxiety-like behaviors and social deficits. CircAnk3 was predominantly located in the cytoplasm of neuronal cells and functioned as a miR-7080-3p sponge to regulate the expression of IQ motif containing GTPase activating protein 1 (Iqgap1). Inhibition of miR-7080-3p or restoration of Iqgap1 in the hippocampus ameliorated the behavioral deficits of circAnk3^+/- mice. Furthermore, circAnk3 deficiency decreased the expression of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2a and impaired the structural plasticity of dendritic synapses in the hippocampus.

Conclusion

Our results reveal an important role of the circAnk3/miR-7080-3p/IQGAP1 axis in maintaining the structural plasticity of hippocampal synapses. CircAnk3 might offer new insights into the involvement of circRNAs in neuropsychiatric disorders.