Abstract
Cerebral ischemia and its sequelae, which include memory impairment, constitute a leading cause of disability worldwide. Micro-RNAs (miRNA) are evolutionarily conserved short-length/noncoding RNA molecules recently implicated in adaptive/maladaptive neuronal responses to ischemia. Previous research independently implicated the miRNA-132/212 cluster in cholinergic signaling and synaptic transmission, and in adaptive/protective mechanisms of neuronal responses to hypoxia. However, the putative role of miRNA-132/212 in the response of synaptic transmission to ischemia remained unexplored. Using hippocampal slices from female miRNA-132/212 double-knockout mice in an established electrophysiological model of ischemia, we here describe that miRNA-132/212 gene-deletion aggravated the deleterious effect of repeated oxygen-glucose deprivation insults on synaptic transmission in the dentate gyrus, a brain region crucial for learning and memory functions. We also examined the effect of miRNA-132/212 gene-deletion on the expression of key mediators in cholinergic signaling that are implicated in both adaptive responses to ischemia and hippocampal neural signaling. miRNA-132/212 gene-deletion significantly altered hippocampal AChE and mAChR-M1, but not α7-nAChR or MeCP2 expression. The effects of miRNA-132/212 gene-deletion on hippocampal synaptic transmission and levels of cholinergic-signaling elements suggest the existence of a miRNA-132/212-dependent adaptive mechanism safeguarding the functional integrity of synaptic functions in the acute phase of cerebral ischemia.
Highlights
Licensee MDPI, Basel, Switzerland.Oxygen is a key determinant of mammalian life and severe oxygen deprivation is most often its antithesis
The dentate gyrus circuitry has the capacity to respond to fast repetitive stimulation via the perforant pathway with a decrease of neurotransmitter release, which can be assessed by delivering a succession of two pulses of increasing interstimulus intervals and quantifying the paired pulse inhibition (PPI) [57,58]
We described for the first time an involvement of the miRNA 132/212 cluster in the acute response of synaptic transmission to repeated ischemia reperfusion insults in the mammalian hippocampus, using an ex vivo electrophysiological approach
Summary
Licensee MDPI, Basel, Switzerland.Oxygen is a key determinant of mammalian life and severe oxygen deprivation is most often its antithesis. Oxygen deprivation accompanied by a sudden disruption of substrate delivery to brain tissue, as occurring in the form of ischemic stroke, triggers a devastating cascade of pathophysiological events, culminating in irreversible dysfunction and loss of CNS tissue [1]. In an effort to illuminate pathophysiological hallmarks of ischemic brain injury and establish novel therapeutic targets, micro-RNAs (miRNAs) have entered the spotlight of scientific inquiry (e.g., see [5,6,7,8,9] for a review). Rising evidence on the differential regulation of miRNAs in the course of cerebral ischemia-reperfusion injuries has led to a vivid debate on their mechanistic functions in the pathophysiology of ischemia–reperfusion insults and their putative role as biomarkers, and detrimental or neuroprotective agents [5,6,7,8,9,32]
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