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Summary: Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.

Abstract Hypoxia induces changes in the secretion of extracellular vesicles (EVs) in several non‐neuronal cells and pathological conditions. EVs are packed with biomolecules, such as microRNA(miR)‐21‐5p, which respond to hypoxia. However, the true EV association of miR‐21‐5p, and its functional or biomarker relevance, are inadequately characterised. Neurons are extremely sensitive cells, and it is not known whether the secretion of neuronal EVs and miR‐21‐5p are altered upon hypoxia. Here, we characterised the temporal EV secretion profile and cell viability of neurons under hypoxia. Hypoxia induced a rapid increase of miR‐21a‐5p secretion in the EVs, which preceded the elevation of hypoxia‐induced tissue or cellular miR‐21a‐5p. Prolonged hypoxia induced cell death and the release of morphologically distinct EVs. The EVs protected miR‐21a‐5p from enzymatic degradation but a remarkable fraction of miR‐21a‐5p remained fragile and non‐EV associated. The increase in miR‐21a‐5p secretion may have biomarker potential, as high blood levels of miR‐21‐5p in stroke patients were associated with significant disability at hospital discharge. Our data provides an understanding of the dynamic regulation of EV secretion from neurons under hypoxia and provides a candidate for the prediction of recovery from ischemic stroke.