Role of miR-9-5p in dendritic remodeling of hippocampal pyramidal neurons: the effect of stress and fast-acting antidepressant ketamine

Stress is a major risk factor in the onset of neuropsychiatric diseases including mood disorders. Stress-based animal models of depression have shown dendritic atrophy and spine remodeling in the hippocampus (HPC), suggesting that stress-induced maladaptive changes have a primary role in the psychopathology. Recent studies showed that a single sub-anesthetic dose of ketamine (KET) exerts a fast and sustained antidepressant effect, accompanied by a rapid reverse of synaptic deficits. However, the molecular mechanisms that underlie the functional and morphological changes induced by stress and KET are still largely unknown. MicroRNA (miRNAs) have emerged as regulators of complex patterns of gene/protein expression changes in the brain and recent studies showed their involvement in the pathophysiology of mood disorders and in the action of psychotropic drugs. Their peculiar ability to fine-tune the expression of hundreds of genes makes them potential candidates as fast mediators of stress-response and KET action. Here we used the Chronic Mild Stress (CMS) animal model of depression and in vitro primary HPC cultures to study whether mechanisms of stress response and KET fast antidepressant action involved changes in dendrite remodeling of HPC pyramidal neurons, together with alteration in the expression of miRNAs known to play a role in neuroplasticity and stress response. Morphological analysis of CA3 pyramidal neurons showed, selectively in animals vulnerable to CMS, a reduction in total length and branching of apical dendrites; KET completely restored these changes. At a molecular level, the expression of miR-9-5p, a brain-enriched miRNA previously associated with neuronal morphology regulation, was selectively decreased in vulnerable animals, while KET recovered the reduction. Further, treatment of primary HPC neurons with corticosterone reduced both dendritic length and miR-9-5p levels; KET fully reversed the changes. By modulating miR-9-5p expression in primary HPC neurons, we demonstrated its direct effect on dendrites and spines remodeling. Bioinformatic analysis followed by in vitro validation identified REST and SIRT1 as biological targets of miR-9-5p. Their expression was further measured in both stress-based models. Our results suggest a role for miR-9-5p in stress-induced dendritic remodeling of pyramidal neurons and in the synaptic restorative action of the antidepressant KET.