Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder.

Mol Psychiatry
Authors
Keywords
Abstract

Bipolar disorder (BD) is a heritable neuropsychiatric disorder with largely unknown pathogenesis. Given their prominent role in brain function and disease, we hypothesized that microRNAs (miRNAs) might be of importance for BD. Here we show that levels of miR-34a, which is predicted to target multiple genes implicated as genetic risk factors for BD, are increased in postmortem cerebellar tissue from BD patients, as well as in BD patient-derived neuronal cultures generated by reprogramming of human fibroblasts into induced neurons or into induced pluripotent stem cells (iPSCs) subsequently differentiated into neurons. Of the predicted miR-34a targets, we validated the BD risk genes ankyrin-3 (ANK3) and voltage-dependent L-type calcium channel subunit beta-3 (CACNB3) as direct miR-34a targets. Using human iPSC-derived neuronal progenitor cells, we further show that enhancement of miR-34a expression impairs neuronal differentiation, expression of synaptic proteins and neuronal morphology, whereas reducing endogenous miR-34a expression enhances dendritic elaboration. Taken together, we propose that miR-34a serves as a critical link between multiple etiological factors for BD and its pathogenesis through the regulation of a molecular network essential for neuronal development and synaptogenesis.

Year of Publication
2015
Journal
Mol Psychiatry
Volume
20
Issue
5
Pages
573-84
Date Published
2015 May
ISSN
1476-5578
URL
DOI
10.1038/mp.2014.176
PubMed ID
25623948
PubMed Central ID
PMC4414679
Links
Grant list
R21 MH087896 / MH / NIMH NIH HHS / United States
R01 MH091115 / MH / NIMH NIH HHS / United States
R33 MH087896 / MH / NIMH NIH HHS / United States
R33MH087896 / MH / NIMH NIH HHS / United States
R21 MH093958 / MH / NIMH NIH HHS / United States
R21MH093958 / MH / NIMH NIH HHS / United States
R01MH095088 / MH / NIMH NIH HHS / United States
R01MH091115 / MH / NIMH NIH HHS / United States
R01 MH095088 / MH / NIMH NIH HHS / United States