Bipolar disorder (BD), characterized by recurrent mood swings between depression and
mania, is a highly heritable and devastating
mental illness with poorly defined pathophysiology. Recent genome-wide molecular genetic studies have identified several
protein-coding genes and
microRNAs (
miRNAs) significantly associated with BD. Notably, some of the
proteins expressed from BD-associated genes function in neuronal synapses, suggesting that abnormalities in synaptic function could be one of the key pathogenic mechanisms of BD. In contrast, however, the role of BD-associated
miRNAs in disease pathogenesis remains largely unknown, mainly because of a lack of understanding about their target mRNAs and pathways in neurons. To address this problem, in this study, we focused on a recently identified BD-associated but uncharacterized
miRNA, miR-1908-5p. We identified and validated its novel target genes including DLGAP4, GRIN1, STX1A, CLSTN1 and GRM4, which all function in neuronal glutamatergic synapses. Moreover, bioinformatic analyses of human brain expression profiles revealed that the expression levels of miR-1908-5p and its synaptic target genes show an inverse-correlation in many brain regions. In our preliminary experiments, the expression of miR-1908-5p was increased after chronic treatment with
valproate but not
lithium in control human neural progenitor cells. In contrast, it was decreased by
valproate in neural progenitor cells derived from dermal fibroblasts of a BD subject. Together, our results provide new insights into the potential role of miR-1908-5p in the pathogenesis of BD and also propose a hypothesis that neuronal synapses could be a key converging pathway of some BD-associated
protein-coding genes and
miRNAs.