The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

Abstract

Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genomewide significance level. However, the functional consequence of these risk alleles is unknown. Here, we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes downregulation of the presynaptic target genes, Complexin-1 (Cplx1), Nsf, and Synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain-of-function results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.

MicroRNAs in neural development: from master regulators to fine-tuners

“…the relative anatomical or physiological strength of connections from either eye to individual cells in the primary visual cortex) and affects the maturation of dendritic spines (Mellios et al, 2011;Tognini et al, 2011). Thus, these studies showed for the first time a function of (Wright et al, 2016;Siegert et al, 2015;Lett et al, 2013) Idiopathic autism Multiple miRNAs (Wu et al, 2016;Mor et al, 2015;Mundalil Vasu et al, 2014) Fragile-X syndrome miR-9, miR-124 ) let-7b/c, miR-125a, miR-181a, miR-296, miR-342 (Wan et al, 2016 miR-125b, miR-132 (Edbauer et al, 2010) miR-125a (Muddashetty et al, 2011) miR-181d (Wang et al, 2015 Rett syndrome miR379-410 cluster and other miRNAs (Wu et al, 2010) let-7f (Mellios et al, 2014) miR132-212 cluster (Im et al, 2010) 377 miRNAs (e.g. miR-134, miR-383, miR-382, miR-182) (Cheng et al, 2014) miR-199a (Tsujimura et al, 2015) miRNAs in the activity-dependent maturation of neural circuits, a form of developmental synaptic plasticity, in the mammalian brain in vivo.…”

“…Moreover, it was reported that decreased levels of miR-137 lead to increased expression of hundreds of genes associated with synaptic transmission and synaptogenesis (Strazisar et al, 2015), suggesting excessive synaptic function as a possible result of MIR137 mutation. Accordingly, miR-137 gain of function in multiple cell lines was shown in another study to lead to decreased mRNA translation of numerous mRNAs encoding presynaptic proteins (Siegert et al, 2015), which in turn resulted in impaired presynaptic function due to a decreased number of neurotransmitter vesicles close to the synaptic cleft (Siegert et al, 2015). Intriguingly, miR-137 function is not restricted to the presynapse: miR-137 was also shown to target mRNA encoding the AMPA-type glutamate receptor subunit GluA1 (Olde Loohuis et al, 2015).…”

“…Interest in miR-137 was sparked by results from a largescale genome-wide association study of schizophrenia patients, which revealed that single nucleotide polymorphisms (SNPs) located in the MIR137 gene were among the most significant SNPs associated with the disease [Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, 2011]. Later, by expressing sequences with specific SNPs in either SH-SY5Y stable cell lines or in neurons induced from human fibroblasts, it was shown that individual SNPs within or in close vicinity of the MIR137 gene could either decrease (Strazisar et al, 2015) or increase (Siegert et al, 2015) miR-137 levels, suggesting that tight regulation of miR-137 is crucial for correct brain function. Moreover, it was reported that decreased levels of miR-137 lead to increased expression of hundreds of genes associated with synaptic transmission and synaptogenesis (Strazisar et al, 2015), suggesting excessive synaptic function as a possible result of MIR137 mutation.…”

Transcription factor 4 gene rs9960767 polymorphism in bipolar disorder

“…It interacts with other genes and forms a transcriptional network to regulate differentiation in various cell types. The TCF4 gene has been identified as a target for the microRNA 137 (miR137) gene product, miRNA137, which is asociated with schizophrenia and severe cognitive abnormalities (21). miR137 is involved in neurogenesis and neuronal differentiation.…”

Emerging roles for miRNA-based post-transcriptional regulation in neuronal morphogenesis and neurodevelopmental disorders

“…Moreover, functional MRI (fMRI) studies have demonstrated that variation in miR-137 specifically influences the activity of the posterior right medial frontal gyrus during a cognitive task and functional connectivity of the front-amygdala and dorsolateral prefrontal-hippocampus in emotional tasks [36,37] . Another study has also shown that increased miR-137 expression levels lead to the downregulation of presynaptic target genes such as complexin-1 (Cplx1) and synaptotagmin-1 (Syt1) in vitro and in vivo, causing impairments of synaptic vesicle trafficking and alterations in synaptic plasticity [38] .…”