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. 2014 Jan 27;9(1):e86469.
doi: 10.1371/journal.pone.0086469. eCollection 2014.

Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects

Neil R Smalheiser  1 , Giovanni Lugli  1 , Hui Zhang  1 , Hooriyah Rizavi  1 , Edwin H Cook  1 , Yogesh Dwivedi  1
Affiliations

Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects

Neil R Smalheiser et al. PLoS One. .

Abstract

Because of the role played by miRNAs in post-transcriptional regulation of an array of genes, their impact in neuropsychiatric disease pathophysiology has increasingly been evident. In the present study, we assessed microRNA expression in prefrontal cortex (Brodmann area 10) of a well-characterized cohort of major depressed, bipolar, and schizophrenia subjects (obtained from Stanley Neuropathology Consortium; n = 15 in each group), using high throughput RT-PCR plates. Discrete miRNA alterations were observed in all disorders, as well as in suicide subjects (pooled across diagnostic categories) compared to all non-suicide subjects. The changes in the schizophrenia group were partially similar to those in the bipolar group, but distinct from changes in depression and suicide. Intriguingly, those miRNAs which were down-regulated in the schizophrenia group tended to be synaptically enriched, whereas up-regulated miRNAs tended not to be. To follow this up, we purified synaptosomes from pooled samples of the schizophrenia vs. control groups and subjected them to Illumina deep sequencing. There was a significant loss of small RNA expression in schizophrenia synaptosomes only for certain sequence lengths within the miRNA range. Moreover, 73 miRNAs were significantly down-regulated whereas only one was up-regulated. Strikingly, across all expressed miRNAs in synaptosomes, there was a significant inverse correlation between the fold-change of a given miRNA seen in schizophrenia and its synaptic enrichment ratio observed in controls. Thus, synaptic miRNAs tended to be down-regulated in schizophrenia, and the more highly synaptically enriched miRNAs tended to show greater down-regulation. These findings point to some deficit in miRNA biogenesis, transport, processing or turnover in schizophrenia that is selective for the synaptic compartment. A novel class of ncRNA-derived small RNAs, shown to be strongly induced during an early phase of learning in mouse, is also expressed in man, and at least one representative (SNORD85) was strongly down-regulated in schizophrenia synaptosomes.

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Conflict of interest statement

Competing Interests: Co-author Neil R. Smalheiser is a PLOS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Manual RT-PCR measurements of 3 selected miRNAs agree very well with measurements performed by TLDA assay.
The control and schizophrenia samples of Experiment 1 were measured using individual TaqMan primer sets for miR-17, miR-145-5p and miR-219-2-3p. Note that lower Ct values indicate higher abundance on a log2 scale (i.e., a decrease of 0.5 Ct represents a 41% increase in abundance or 1.41-fold difference across groups). Error bars indicate standard error of the mean. In this assay, miR-17-5p showed a 1.18-fold increase (p = 0.05), which is very close to 1.22-fold reported in Table 1. miR-145-5p showed a 0.85-fold change (p = 0.16), similar to 0.68-fold in Table 1. miR-219-2-3p showed a 1.60-fold increase (p = 0.029), similar to 1.48-fold in Table 1.
Figure 2
Figure 2. Human PFC sample processed for synaptosome isolation and examined for protein and total RNA.
(A) Equal amount of proteins (12 µg) were subjected to PAGE and blotted with anti-PSD95 (Millipore mouse monoclonal clone 28/43; 1∶30,000), anti-Synapsin I (Chemicon AB1543P, lot #LV1354224, rabbit polyclonal affinity purified; 1∶30,000), or anti-PCNA (Sigma, P-8825, clone PC10, mouse monoclonal; 1∶1000) antibody. Fractions are: T, total homogenate; S2, 20,000×20 min supernatant; Syn, synaptosomes. The raw data are shown in File S5. (B) Synaptosomal RNA (0.5 µg) was loaded in a 0.9% TBE Agarose gel and stained with Ethidium Bromide. MW is the 1 Kb plus ladder size markers.
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