miR-135a Regulates Synaptic Transmission and Anxiety-Like Behavior in Amygdala

Abstract

MicroRNAs are a class of non-coding RNAs with a growing relevance in the regulation of gene expression related to brain function and plasticity. They have the potential to orchestrate complex phenomena, such as the neuronal response to homeostatic challenges. We previously demonstrated the involvement of miR-135a in the regulation of early stress response. In the present study, we examine the role of miR-135a in stress-related behavior. We show that the knockdown (KD) of miR-135a in the mouse amygdala induces an increase in anxiety-like behavior. Consistently with behavioral studies, electrophysiological experiments in acute brain slices indicate an increase of amygdala spontaneous excitatory postsynaptic currents, as a result of miR-135a KD. Furthermore, we presented direct evidences, by in vitro assays and in vivo miRNA overexpression in the amygdala, that two key regulators of synaptic vesicle fusion, complexin-1 and complexin-2, are direct targets of miR-135a. In vitro analysis of miniature excitatory postsynaptic currents on miR-135a KD primary neurons indicates unpaired quantal excitatory neurotransmission. Finally, increased levels of complexin-1 and complexin-2 proteins were detected in the mouse amygdala after acute stress, accordingly to the previously observed stress-induced miR-135a downregulation. Overall, our results unravel a previously unknown miRNA-dependent mechanism in the amygdala for regulating anxiety-like behavior, providing evidences of a physiological role of miR-135a in the modulation of presynaptic mechanisms of glutamatergic neurotransmission.

microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

“…We observed opposing effects of mir-598-3p inhibition in FC (anxiolytic-like) and SR (anxiogenic-like) mice in the OFT. Interestingly, Dicer1 knockdown [23] and miR-135a inhibition [42,43] in the amygdala were anxiogenic-like in the EPM. In the absence of a background of stress, miRNAs have been hypothesized to influence anxiety-like behavior potentially through metabolic or inflammatory mechanisms as several miRNAs, for example mir-34c and mir-26a family miRNAs, are implicated in both changes in inflammation and the modulation of anxiety-like behavior [23,24,44].…”

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

“…Multiple miRNAs have been previously reported to regulate synaptic fusion-related proteins at the mRNA level. For example, miR-153 regulates Snap25, Vamp2, Snca, Trak2, Bsn and Pclo genes at the mRNA level [23]; miR-137 inhibits complexin-1, Nsf and Syt1 in mouse model of schizophrenia [20]; miR-34c targets VAMP-2 [21] and miR-135a binds the complexin-1 and complexin-2 genes in the amygdala [22]. To identify which one of the above miRNAs is involved in the CBH induced downregulation of fusion-related proteins in the hippocampi of rats, we performed qRT-PCR test.…”

“…Previous studies have reported that microRNAs (miR-NAs) could regulate presynaptic plasticity by targeting various vesicle-related proteins. For example, miR-137 impaired vesicle release in a mouse model of schizophrenia [20]; miR-34c was reported mediate amyloid-beta (Aβ)-induced synaptic failure by targeting VAMP2 [21]; knockdown of miR-135a triggered an early stress response by disturbing presynaptic vesicle release [22]; miR-153 was found to be a contextual fear-induced miRNA in the dentate gyrus [23] and was reported to regulate vesicle release in zebrafish [24]. However, these studies did not analyze CBH-induced changes in miRNA levels or their function in presynaptic plasticity.…”

Genome and stress-reaction in animals and humans

“…MiR-34 в клетках амигдалы при стрессе инициирует процессы нейропластичности [132], а активация там же изоформы miR-34c регулирует активность гена Crfr1 (рецептора 1 кортикотропин-рилизинг-фактора), тем самым ослабляя стресс-реакцию и тревожное поведе-ние у мышей [133]. Изоформа miR-135a модулирует пресинаптические механизмы глутаматергической ней-ротрансмиссии в нейронах амигдалы, тем самым регу-лируя тревожность стрессированных животных [134]. Модуляция экспрессии регуляторных молекул семейст-ва некодирующих РНК, в частности miR-34c, в клетках гипоталамуса может быть связана с развитием ПТСР у человека [135].…”