The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex
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Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent linear forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following MD. Knockdown of circHomer1 prevented the depression of closed-eye responses normally observed after 3-day MD. circHomer1 -knockdown led to a reduction in average dendritic spine size prior to MD, but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1 - knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1 -knockdown neurons, suggesting that circHomer1 regulates plasticity through mechanisms of activity-dependent AMPA receptor endocytosis. Thus, activity-dependent circRNAs regulate developmental synaptic plasticity, and our findings highlight the essential role of circHomer1 in V1 plasticity induced by short-term MD.
Significance Statement
Circular RNAs (circRNAs) are a class of closed-loop RNAs formed through back- splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in synaptic function and plasticity remain poorly understood. We conducted an in vivo transcriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in visual cortex and found that circHomer1 , a circRNA derived from the Homer1 gene, is critical for functional plasticity in vivo . Developmentally regulated circHomer1 mediates synaptic plasticity via Arc-mediated endocytosis of AMPA receptors. Our findings demonstrate circRNA regulation during experience-dependent plasticity and reveal their functional significance and mechanism.
