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Am J Transl Res 2013;5(4):450-464
Original Article
Mood stabilizer-regulated miRNAs in neuropsychiatric and
neuro-degenerative diseases: identifying associations and functions
Joshua G Hunsberger, Emily B Fessler, Fairouz L Chibane, Yan Leng, Dragan Maric, Abdel G Elkahloun, De-Maw
Chuang
Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health,
Bethesda, MD, USA; National Hu-man Genome Research Institute (NHGRI), National Institutes of Health,
Bethesda, MD, USA; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of
Health, Bethesda, MD, USA
Received April 4, 2013; Accepted April 27, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: 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.
(AJTR1304005).
Keywords: microRNA, neuroprotection, glutamate excitotoxicity, lithium, valproic acid, mood stabilizers
Address correspondence to: Dr. De-Maw Chuang, 10 Center Drive MSC 1363, NIMH, NIH Bethesda, MD,
20892-1363, USA. Tel: 301-496-4915; Fax: 301-480-9290; E-mail: chuang@mail.nih.gov; Dr. Joshua Hunsberger,
10 Center Drive MSC 1363, NIMH, NIH, Bethesda, MD, USA. 20892-1363, Tel: 301-496-6798; E-mail:
hunsbergerj@mail.nih.gov
Original Article
Mood stabilizer-regulated miRNAs in neuropsychiatric and
neuro-degenerative diseases: identifying associations and functions
Joshua G Hunsberger, Emily B Fessler, Fairouz L Chibane, Yan Leng, Dragan Maric, Abdel G Elkahloun, De-Maw
Chuang
Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health,
Bethesda, MD, USA; National Hu-man Genome Research Institute (NHGRI), National Institutes of Health,
Bethesda, MD, USA; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of
Health, Bethesda, MD, USA
Received April 4, 2013; Accepted April 27, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: 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.
(AJTR1304005).
Keywords: microRNA, neuroprotection, glutamate excitotoxicity, lithium, valproic acid, mood stabilizers
Address correspondence to: Dr. De-Maw Chuang, 10 Center Drive MSC 1363, NIMH, NIH Bethesda, MD,
20892-1363, USA. Tel: 301-496-4915; Fax: 301-480-9290; E-mail: chuang@mail.nih.gov; Dr. Joshua Hunsberger,
10 Center Drive MSC 1363, NIMH, NIH, Bethesda, MD, USA. 20892-1363, Tel: 301-496-6798; E-mail:
hunsbergerj@mail.nih.gov
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