Upregulation of miR-19b-3p exacerbates chronic stress-induced changes in synaptic plasticity and cognition by targeting Drebrin.

Chronic stress is associated with impairment of synapse plasticity in hippocampus and cognitive dysfunction in rodent and human. Notably, corticosterone (CORT) is believed to take responsibility for dendritic atrophy and reduction of spine number induced by chronic stress in hippocampus. But little is known about the molecular mechanisms underlying CORT induced abnormal synapse plasticity and cognitive dysfunction. Drebrin is an F-actin binding protein that modulates memory formation and maintenance by controlling the genesis and morphology of dendritic spines. In addition, miRNAs have been reported to participate in the negative regulation of protein-coding genes. In this study, five miRNAs capable of targeting Drebrin were selected by searching miRNA databases. One of these miRNAs, miR-19b-3p, was found to be upregulated in the hippocampal neurons of mice with chronic restraint stress (CRS). Luciferase reporter assay and Fluorescence in situ hybridization (FISH) were employed to identify the interaction between miR-19b-3p and Drebrin. In addition, silencing miR-19b-3p expression in vivo using an antagomir or in vitro using an inhibitor increased Drebrin expression, ameliorated the abnormal dendritic structure and upregulated the spine density in hippocampal CA1 pyramidal neurons of CRS mice and primary hippocampal neurons cultured under CORT stimulation, respectively. Electrophysiological analysis revealed that inhibition of miR-19b-3p rescued the limited synaptic transmission and synaptic plasticity in hippocampal neurons. Moreover, blocking miR-19b-3p drastically protected against cognitive deficits in CRS mice. These in vivo and in vitro findings indicate that the upregulation of miR-19b-3p exacerbates CRS-induced abnormal synaptic plasticity and cognitive impairment by targeting Drebrin.