Effects of microRNA-181b-5p on cognitive deficits in first-episode patients with schizophrenia: Mediated by BCL-2
Introduction
Cognitive impairment is a core trait of schizophrenia (DeTore et al., 2019; Kahn and Keefe, 2013). Poor quality of social relationships, declining self-care skills, and reduced capacity for independent living result from the decreased attention levels, working memory, verbal learning and memory, reasoning and problem solving, speed of processing, and executive functioning typical of this condition (DeTore et al., 2019; Green et al., 2015; Marder, 2006). Additionally, cognitive deficits potentially predict the attenuated response of some therapeutic approaches to schizophrenia (Kurtz, 2011). However, antipsychotic treatments have limited efficacy in ameliorating the cognitive symptoms in schizophrenia. Therefore, it is necessary to identify cognition-enhancing strategies (Murueta-Goyena et al., 2019).
MicroRNAs (miRNAs) are endogenous non-coding RNAs whose major function is to silence their target mRNAs (Alacam et al., 2016; He et al., 2018; Olde Loohuis et al., 2015). Cognitive impairment in schizophrenia is thought to be associated with miRNAs and their regulatory networks, which could impair synaptic plasticity (Hansen et al., 2013; Hutsler and Zhang, 2010; Ma et al., 2014; Olde Loohuis et al., 2015). Abnormal expression of miRNAs, such as miR-17-92, leads to impaired cognitive function (Pan et al., 2019) and adult neuronal stem cells (Szulwach et al., 2010). More than half of all known miRNAs are highly or exclusively expressed in the brain and regulate neuronal genes involved in development and functions of this organ (Hansen et al., 2013; Ma et al., 2014; Olde Loohuis et al., 2015).
The expression patterns of miRNAs depend on the type of cell, regions, development stage, and environmental context (Woldemichael and Mansuy, 2016). In addition to miRNAs in the brain, miRNAs in peripheral blood are also associated with schizophrenia (Woldemichael and Mansuy, 2016). Several miRNAs, such as miR-181b, miR-30e, miR-34a, and miR-7, are considered to be involved in the pathogenesis of schizophrenia; their expression levels in schizophrenia patients were shown to be significantly higher than those in normal control groups (Song et al., 2014). MiR-181b level, in particular, was lowered by antipsychotic treatment, in parallel with improvement of symptoms (Song et al., 2014). Moreover, miR-181b, which was first identified in neuronal cells, was expressed at significantly higher level in postmortem cortical grey matter of the superior temporal gyrus of schizophrenia patients than in healthy controls (Beveridge et al., 2008). Other studies indicate that miR-181b is also expressed in nonneuronal brain cells and functions as an inhibitor of proliferation and a promoter of apoptosis, which is dampened in glioma as well as other cancers (Huang et al., 2015; Lin et al., 2018; Zhang et al., 2019).
The anti-apoptotic gene BCL-2 (B-cell lymphoma 2) may represent a direct and crucial target of miR-181b-5p (Zhang et al., 2019). A previous study using a dual luciferase reporter assay showed that miR-181b-5p targeted the 3′UTR of BCL-2 mRNA in chemo-sensitive glioma cells (Zhang et al., 2019). BCL-2 protein localizes to the mitochondrial outer membrane, nuclear membrane, and parts of the endoplasmic reticulum. It regulates neural survival, suppresses programmed cell death in primary neurons by preventing cells from entering the apoptotic pathway (Chan and Yew, 1998). Neuronal apoptosis elicits synaptic loss which then exacerbates death of neurons and contributes to schizophrenia pathophysiology (Jarskog et al., 2005). The expression of BCL-2 differs across brain regions, with high level observed in the superficial layers of the piriform cortex, pyramidal neurons of the hippocampus, cholinergic neurons of the nucleus basalis of Meynert, the amygdala, and the olfactory bulb (Castre N et al., 1994; López et al., 1999; Merry et al., 1994; Vyas et al., 1997), suggesting it may have relevance to cognitive function. Therefore, we hypothesized that miR-181b-5p exerts its effect on cognitive impairment via downregulating BCL-2 expression.
Section snippets
Subjects
We recruited 123 first-episode patients with schizophrenia (FEPS) from the Beijing Huilongguan Hospital. The inclusion criteria were as follows: (a) meeting criteria for diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV); (b) between 18 and 45 years old; (c) illness duration less than 3 years and antipsychotic treatment duration within 2 weeks. The medication status of patients included, drug naïve (10), haloperidol (2),
Demographics and clinical characteristics
There were no significant differences between FEPS and HCs in age and sex ratio; however, HCs had significantly higher education levels than FEPS (p = 0.012) (Table 1).
Relationship between miR-181b-5p and BCL-2
Compared with HCs, FEPS had upregulated level of miR-181b-5p (p = 0.001) (Table 2), and the levels of BCL-2 mRNA and protein were downregulated in FEPS compared to HCs (p = 0.002 and 0.023) (Table 2). The level of miR-181b-5p was negatively associated with BCL-2 mRNA level in FEPS (r = −0.356, p < 0.001) (Fig. 1), but not with
Discussion
In this study, we found that the expression level of miR-181b-5p in peripheral blood of FEPS was significantly higher than that in HCs. This finding was consistent with the reported result in schizophrenia brain tissue, such as temporal cortex (Beveridge et al., 2008) and dorsolateral prefrontal cortex (Beveridge et al., 2010), as well as in plasma (Song et al., 2014). Although no studies on the expression pattern of miR-181b-5p in the cerebrospinal fluid (CSF) of schizophrenia have been
Author statement
Yunlong Tan: Conceptualization, Methodology, Writing-Review and Editing, Supervision, Funding acquisition. Li Tian: Writing-Review and Editing, Funding acquisition. Mengzhuang Gou: Data curation, Writing-Original draft preparation. Shujuan Pan, Jinghui Tong, Yanfang Zhou, Jiarui Han, Ting Xie, Ting Yu, Wei Feng, Ping Zhang, Junchao Huang: Resources. Yanli Li, Song Chen, Yimin Cui, Baopeng Tian, Shuping Tan, Zhiren Wang, Xingguang Luo, Chiang-Shan R. Li, L.Elliot Hong: Writing-Review and Editing.
Declaration of competing interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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