*2.2. miRNAs and BDNF*

MicroRNAs (miRNAs) are a class of evolutionary conserved small non-coding single-strand RNA molecules, 18–25 nucleotide long, able to bind to 3 untranslated regions (3 UTR) of target mRNAs and promote their degradation or suppress their translation into proteins. MiRNAs are expressed abundantly within the nervous system in a tissue-specific manner and are crucial players in several biological processes, including neurogenesis, neuronal maturation, synapse formation, axon guidance, neurite outgrowth and neuronal plasticity [51–53]. Accumulating data indicate that synthesis of BDNF may be affected by miRNAs, indeed, a regulatory negative feedback loop between BDNF and miRNAs exists. That is, while BDNF treatment stimulates neuronal miRNAs expression, miRNAs generally inhibit the expression of BDNF [54]. This negative feedback loop is maintained in a state of equilibrium

in normal cells. Alterations in miRNAs or in BDNF contribute to the pathogenic mechanisms involved in neurodegenerative diseases or neuropsychiatric disorders.

A number of recent studies, obtained from high throughput sequencing screening of different brain regions or from neurological disorders, have identified seven miRNAs (miR-15a, miR-206, miR-155-5p, miR-16, miR-103-3p, miR-330-3p, Let-7a-3p) correlated with BDNF [55]. Previous data published by Schratt et al. reported the involvement of miR-134 in BDNF-regulated dendritic spine size in hippocampal neurons. They demonstrate that miR-134 negatively regulates the spine size via repressing the translation of LIM kinase 1, which is known to regulate dendritic structures. BDNF is able to relieve the inhibition of LIM kinase 1 translation, and in this manner contribute to synaptic development, maturation and/or plasticity [56]. Recently, Baby et al. [57] found that miR-134 mediates post-transcriptional regulation of CREB1 and BDNF, as previously described by Gao et al. [58], who demonstrated that mutant mice lacking Sirtuin 1 (SIRT1) catalytic activity shows reduction in both CREB and BDNF proteins and upregulation of miR-134. Thus, higher levels of miR-134 negatively regulate synaptic plasticity [58]. MiR-134-mediated post-transcriptional regulation of CREB1 and BDNF prevents cognitive deficits in chronic unpredicted mild stress model (CUMS) [59]. At the same time, data published by Xin and coworkers [60] demonstrate that miR-202-3p silencing reduces the damage to hippocampal nerve in CUMS rats through the upregulation of BNDF expression. miRNAs could be an effective target also for the treatment of depression. Recent data demonstrate that miR-124-mediated post-transcriptional regulation of CREB1 and BDNF can improve depression-like behavior in a rat model [61]. Instead, miR-153 through the inhibition of activation of the JAK-STAT signaling pathway improves BDNF expression and influences the proliferative ability of hippocampal neurons in autistic mice [62].

In vitro studies have also allowed analysis of the effect of neurotoxins or anesthetic agents on miRNAs expression and in turn, on BDNF expression. For instance, differentiated PC12 cells, treated with 1-methyl-4-phenylpyridinium (MPP), show upregulation of miR-34a, miR-141, and miR-9, suggesting that perturbed expression of them may contribute to Parkinson's disease (PD)-related pathogenic processes, probably by affecting the expression of B-cell lymphoma 2 (BCL2), BDNF, and SIRT1 as potential targets [63].

Instead, studies in vitro on embryonic stem cell-derived neurons demonstrated that inhibition of miR-375 and miR-107 ameliorates ketamine-induced neurotoxicity via inverse regulation of the BDNF gene [64,65].

In summary, understanding the different functions of the various BDNF transcripts, the modulation of the expression of specific exons, and investigating the function of the BDNF-related miRNAs may represent a promising strategy to restore enduring changes in gene expression in response, for example, to environmental insults. This, in turn, might open new therapeutic perspectives for the treatment of neurodegenerative and neuropsychiatric disorders.
