mir-135a Regulates Synaptic Activity and its Depletion in Amygdala Induces Anxiety-Like Behavior

microRNAs are a class of non coding RNAs with a growing significance in regulatory mechanisms of gene expression related to brain function and plasticity. Recent studies indicate that they potentially orchestrate any complex phenomena sustained by structural and functional plasticity, as learning and memory and neuronal response to homeostatic challenges. We have recently shown that the amygdalar miR-135a is a component of the early stress response, suggesting its function in the activation of corticosteroid signaling, through the regulation of the mineralocorticoid receptor (Mannironi et al, 2013). In this study, we have examined its role in the context of stress-related behavior. We found that depletion of miR-135a in the amygdala of adult mice induced an increase in anxiety in the elevated plus maze. Furthermore, by in vitro studies with neuronal primary cultures, we demonstrated its role in the regulation of synaptic transmission, specifically in the spontaneous neurotransmitter vesicle release. We characterized, as direct targets of miR-135a, complexin-1 and -2 (Cpx1 and Cpx2), key regulators of pre and postsynaptic vesicle fusion, fine-tuners of synaptic activity and plasticity. Specific interactions between miR-135a and Cpx1 and Cpx2 mRNAs were demonstrated. Our findings pinpoint to miR-135a as a general modulator of synaptic plasticity. Overall, our results unravel a previously unknown miRNA-dependent mechanism in amygdala in controlling anxiety-like behavior, suggesting a physiological role of miR-135a in the modulation of stress-related behavior with a possible involvement in the onset of stress-related psychopathologies