Abstract
Altered synaptic plasticity is often associated with major depressive disorder (MDD). Disease-associated changes in synaptic functions are tightly correlated with altered microRNA (miRNA) expression. Here, we examined the role of miRNAs and their functioning at the synapse in MDD by examining miRNA processing machinery at synapse and sequencing miRNAs and analyzing their functions in synaptic and total tissue fractions obtained from dorsolateral prefrontal cortex (dlPFC) of 15 MDD and 15 matched non-psychiatric control subjects. A total of 333 miRNAs were reliably detected in the total tissue fraction. Multiple testing following the Benjamini–Hochberg false discovery rate [FDR] showed that 18 miRNAs were significantly altered (1 downregulated 4 up and 13 downregulated; p < 0.05) in MDD subjects. Out of 351 miRNAs reliably expressed in the synaptic fraction, 24 were uniquely expressed at synapse. In addition, 8 miRNAs (miR-215-5p, miR-192-5p, miR-202-5p, miR-19b-3p, miR-423-5p, miR-219a-2-3p; miR-511-5p, miR-483-5p showed significant (FDR corrected; p < 0.05) differential regulation in the synaptic fraction from dlPFC of MDD subjects. In vitro transfection studies and gene ontology revealed involvement of these altered miRNAs in synaptic plasticity, nervous system development, and neurogenesis. A shift in expression ratios (synaptic vs. total fraction) of miR-19b-3p, miR-376c-3p, miR-455-3p, and miR-337-3p were also noted in the MDD group. Moreover, an inverse relationship between the expression of precursor (pre-miR-19b-1, pre-miR-199a-1 and pre-miR-199a-2) and mature (miR-19b-3p, miR-199a-3p) miRNAs was found. Although not significantly, several miRNA processing enzymes (DROSHA [95%], DICER [17%], TARBP2 [38%]) showed increased expression patterns in MDD subjects. Our findings provide new insights into the understanding of the regulation of miRNAs at the synapse and their possible roles in MDD pathogenesis.
Highlights
Major depressive disorder (MDD) is one of the most debilitating mental disorders worldwide with a lifetime prevalence of 10.8% [1]
RESULTS miRNA changes in total and synaptic fractions of MDD subjects Initially, the synaptic fraction prepared from human dorsolateral prefrontal cortex (dlPFC) was characterized
Our sequencing results in dlPFC showed 333 miRNAs reliably detected in the total fraction of dlPFC; of them, 18 miRNAs were significantly altered in MDD subjects (4 upregulated and 14 downregulated)
Summary
Major depressive disorder (MDD) is one of the most debilitating mental disorders worldwide with a lifetime prevalence of 10.8% [1]. A possible role of miRNA processing machinery locally at the synapse has been suggested for activity-dependent changes in miRNA expression In this regard, it has been shown that is miRNA maturational machinery available at the synapse [10], but that miRNA biogenesis can occur in the postsynaptic densities (PSDs) near synapse [10,11,12]. It has been shown that a subset of miRNAs is expressed at a higher level in synaptic fraction than the whole cell lysate isolated from mouse brain [11], which could be the result of an active mobilization of pre-miRNAs and their cleavage into mature miRNAs near synapse with the help of DICER, TRBP and other processing molecules [10, 13]. Reports indicate the role of local synaptic activity in triggering the release
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