Mood stabilizer-regulated miRNAs in neuropsychiatric and neurodegenerative diseases: identifying associations and functions.

Identifying mechanisms to enhance neuroprotection holds tremendous promise in developing new treatments for neuropsychiatric and neurodegenerative diseases. We sought to determine the potential role for microRNAs (miRNAs) in neuroprotection following neuronal death. A neuronal culture system of rat cerebellar granule cells was used to examine miRNA expression changes following glutamate-induced excitotoxicity and neuroprotective treatments. Combination treatment with the mood stabilizers lithium and valproic acid provided near-complete protection from glutamate excitotoxicity. Numerous miRNAs were detected by microarrays to be regulated by the combined lithium and valproic acid treatment, and the following candidates were confirmed using real-time PCR: miR-34a, miR-147b, miR-182, miR-222, miR-495, and miR-690. We then verified the apoptotic actions of miR-34a mimic in a human neuroblastoma cell line (SH-SY5Y) under basal conditions and following endoplasmic reticulum stress. To gain insight into the function of these mood stabilizer-regulated miRNAs, we performed two separate analyses: a candidate approach using Ingenuity Pathway Analysis that was restricted to only our PCR-verified miRNAs, and a global approach using DIANA-mirPath that included all significantly regulated miRNAs. It was observed that the pathways associated with mood stabilizer-regulated miRNAs in our study (global approach) are strongly associated with pathways implicated in neuropsychiatric diseases such as schizophrenia. We also observed an overlap in the mood stabilizer-regulated miRNAs identified from our study along with dysregulated miRNAs in both neuropsychiatric and neurodegenerative disorders. We anticipate that these associations and overlaps implicate critical pathways and miRNAs in disease mechanisms for novel therapeutic treatments that may hold potential for many neurological diseases.