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 genome-wide 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.

MicroRNA-137 Inhibits EFNB2 Expression Affected by a Genetic Variant and Is Expressed Aberrantly in Peripheral Blood of Schizophrenia Patients

“…Reelin signaling was required for the nervous system to function properly, and disruption of this pathway results in lissencephaly, a severe developmental disorder associated with schizophrenia (Costa et al, 2002, Herz and Chen, 2006, Hong et al, 2000). Previous studies have demonstrated that miR-137 regulates adult neurogenesis, neuronal maturation, and presynaptic plasticity (Siegert et al, 2015, Silber et al, 2008, Smrt et al, 2010, Szulwach et al, 2010). Siegert et al showed that overexpression of miR-137 caused impairment in synaptic vesicle trafficking and alterations in synaptic plasticity (Siegert et al, 2015).…”

“…Previous studies have demonstrated that miR-137 regulates adult neurogenesis, neuronal maturation, and presynaptic plasticity (Siegert et al, 2015, Silber et al, 2008, Smrt et al, 2010, Szulwach et al, 2010). Siegert et al showed that overexpression of miR-137 caused impairment in synaptic vesicle trafficking and alterations in synaptic plasticity (Siegert et al, 2015). Using meta gene set enrichment analyses, Wright et al found that potential target gene sets of miR-137 were enriched with variants associated with Ephrin receptor signaling and some other signal pathways (Wright et al, 2015).…”

MiR-218 targets MeCP2 and inhibits heroin seeking behavior

“…Recent studies indicate that epigenetic regulation of gene expression plays an important role in neurogenesis, synaptic plasticity and neurological disorders8910. MicroRNAs (miRNAs) are a class of evolutionarily conserved, 18–25 nucleotide non-coding sequences that post-transcriptionally regulate gene expression.…”

miRNAs in synapse development and synaptic plasticity

“…For example, miR-188 regulates dendritic spine number and mEPSC frequency in hippocampal neurons by targeting the semaphorin-3F receptor Nrp-2 [32]; Drosophila miR-1000 suppresses synaptic glutamate release by targeting the vesicular glutamate transporter (Vglut) [33]; and in addition to GluA1, miR-137 also targets proteins in the synaptic vesicle release machinery including complexin-1, N-thylmaleimide-sensitive fusion protein (Nsf) and synaptotagmin-1 to reduce the number of synaptic vesicles proximal to the release site, and frequency facilitation at the mossy fiber-CA3 synapse [34]. miR-132 is also found to modulate synapse number and mEPSCs [28,35,36], but the underlying mechanism is obscure.…”

“…In addition to regulating 5-HT induced LTF and homeostatic synaptic plasticity, miR-124 inhibits NMDA receptor-dependent LTP by controlling Zif268 translation, and knockdown of miR-124 restores LTP in EPAC (an exchange protein directly activated by cAMP) knockout mice [39]. While miR-137 mediates mGluR-dependent LTD [30], it inhibits the induction of mossy fiber LTP in the hippocampus [34]. miR-132 overexpression inhibits both LTP and carbachol-induced LTD in the perirhinal cortex [40], and deleting miR-132 and miR-212 in mice causes aberrant theta burst-induced LTP [41].…”