Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke.

Abstract

Recent studies have uncovered that accumulation of glutamate after ischaemic stroke is closely associated with the down-regulation of glutamate transporter-1 (GLT-1) expression, suggesting that GLT-1 expression critically controls glutamate accumulation and the abnormal glutamate transport-elicited neuronal cell excitotoxicity in patients with ischaemic stroke. However, it remains unknown how GLT-1 expression is regulated under ischaemic stroke conditions. In the present study, we screened the expression of nine brain-specific or brain-enriched miRNAs in a focal cerebral ischaemia/reperfusion (I/R) injury rat model, which showed glutamate accumulation and down-regulated GLT-1 expression as expected, and revealed that the miR-107 level was elevated in both brain tissue and plasma in the model. Next, we examined the functional relationship of miR-107 with GLT-1 expression in a nerve cell hypoxia/reoxygenation (H/R) injury model. H/R treatment increased apoptosis of the nerve cells concomitant with glutamate accumulation, miR-107 elevation and suppressed GLT-1 expression, mimicking our invivo findings in the cerebral I/R injury rat model invitro. Co-treating the cells with an miR-107 inhibitor blocked all of the effects, demonstrating that miR-107 functions to inhibit GLT-1 expression and elevate glutamate accumulation. To extend these animal and cell-based studies to clinical patients, we measured the plasma levels of miR-107 and glutamate, and observed that both miR-107 and glutamate were elevated in patients with ischaemic stroke. On the basis of these observations, we conclude that elevated miR-107 expression after ischaemic stroke accounts, at least partially, for glutamate accumulation through suppression of GLT-1 expression. Our findings also highlight that the plasma level of miR-107 may serve as a novel biomarker for monitoring excitotoxicity in patients with ischaemic stroke.