CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis

Kaiyu Xu,Jiali Li,Zhengfei Hu,Longbao Lv,Ying Zhang,Yong-Tang Zheng,Wandi Xiong,Zhengbo Wang,Chao Liu,Lin Lu,Zhongyu Zhang,Xin-Tian Hu

doi:10.1038/s41467-020-17435-7

Abstract

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.

Highlights

Circular RNAs are abundant in mammalian brain and some show age-dependent expression patterns
While the molecular mechanism and physiological function of changes in circRNA expression in the biology of brain aging remains unclear, we report here an example of the molecular consequences of such a change
Based on our data from circGRIA1, we propose that age-related increases in circRNA expression are the result of increased noncanonical splicing of newly generated transcripts in postmitotic neurons, and play an important role in the biology of brain aging

Summary

Introduction

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Age-related alterations in neuronal function are partially resulted from changes in homeostatic synaptic plasticity and calcium homeostasis due to such as factors like decreased expression of neurotransmitter receptors and selective ion channel messenger RNAs (mRNAs)[9,10,11,12]. Aging reduced expression of glutamate receptors and their associated second messengers As these play an important role in regulating intracellular calcium they are critical for the maintenance of synaptic plasticity. Cotman et al.[13] noted a 45% loss in glutamate receptors that occur in aged rats when compared with young animals[11,13] Studies such as these are silent on the mechanisms behind this age-related decrease. Our recent work has described dynamic changes in circRNA expression in rhesus macaque brain during aging, and indicated that the complicate correlation between circRNA and host mRNA expression may be involved in the biology of brain aging[26]

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