MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function

Miller, Brooke H.; Zeier, Zane; Li, Xi; Lanz, Thomas A.; Deng, Shibing; Strathmann, Julia; Willoughby, David A.; Kenny, Paul J.; Elsworth, John D.; Lawrence, Matthew S.; Roth, Robert H.; Edbauer, Dieter; Kleiman, Robin J.; Wahlestedt, Claes

doi:10.1073/pnas.1113793109

Cited by 272 publications

(214 citation statements)

References 45 publications

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“…It is of interest that SREB2 is the target of several microRNAs. One of these (miR-137) has been recently associated with schizophrenia in a large genome-wide association study (Ripke et al, 2011), while another (miR-876-3p) has been found to be overexpressed in the DLPFC of patients with bipolar disorder (Miller et al, 2012). In the same report, miR-17-5p expression was found to be dysregulated both in schizophrenia and in bipolar disorder; the evidence for this miRNA binding in the SREB2 locus, however, is weaker for this miRNA (http://www.targetscan.…”

Section: Discussionmentioning

confidence: 99%

Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

Radulescu¹,

Sambataro

Mattay

et al. 2012

Neuropsychopharmacol

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Genetic variants in GPR85 (SREB2: rs56080411 and rs56039557) have been associated with risk for schizophrenia. Here, we test the hypothesis that these variants impact on brain function in normal subjects, measured with functional magnetic resonance imaging (fMRI) paradigms that target regions with greatest SREB2 expression (hippocampal formation and amygdaloid complex). During a facial emotion recognition paradigm, a significant interaction of rs56080411 genotype by sex was found in the left amygdaloid complex (male risk allele carriers showed less activation than male homozygotes for the non-risk allele, while females showed the opposite pattern). During aversive encoding of an emotional memory paradigm, we found that risk allele carriers for rs56080411 had greater activation in the right inferior frontal gyrus. Trends in the same direction were present for rs56039557 in the right occipital cortex and right fusiform gyrus. During a working memory paradigm, a significant sex-by-genotype interaction was found with male risk allele carriers of rs56080411 having inefficient activation within the left dorsolateral prefrontal cortex (DLPFC), compared with same sex non-risk carriers, while females revealed an opposite pattern, despite similar levels of performance. These data suggest that risk-associated variants in SREB2 are associated with phenotypes similar to those found in patients with schizophrenia in the DLPFC and the amygdala of males, while the pattern is opposite in females. The findings in females and during the emotional memory paradigm are consistent with modulation by SREB2 of brain circuitries implicated in mood regulation and may be relevant to neuropsychiatric conditions other than schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

Radulescu¹,

Sambataro

Mattay

et al. 2012

Neuropsychopharmacol

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“…In addition, a subset of BDNF gene promoters in schizophrenia prefrontal cortex cannot be fully accessed by the growth arrest and DNA-damage-inducible, beta GADD45b protein, which coordinates DNA demethylation pathways, resulting in excess DNA methylation and hydroxymethylation of BDNF promoter IX and decreased transcription from that site (Gavin et al, 2012). Likewise, dysregulated expression of DNA methyltransferase DNMT3a and various transcription factors was linked to decreased expression of the NMDA-sensitive small RNA, mIR-132 (Miller et al, 2012).…”

Section: Epigenetics and Transcriptional (Dys) Regulation In Diseasedmentioning

confidence: 99%

Epigenetics in the Human Brain

Houston

Peter

Mitchell

et al. 2012

Neuropsychopharmacol

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Many cellular constituents in the human brain permanently exit from the cell cycle during pre-or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Here, we summarize the current knowledge base as it pertains to genome organization in the human brain, including the regulation of DNA cytosine methylation and hydroxymethylation, and a subset of (altogether 4100) residue-specific histone modifications associated with gene expression, and silencing and various other functional chromatin states. We propose that high-resolution mapping of epigenetic markings in postmortem brain tissue or neural cultures derived from induced pluripotent cells (iPS), in conjunction with transcriptome profiling and whole-genome sequencing, will increasingly be used to define the molecular pathology of specific cases diagnosed with depression, schizophrenia, autism, or other major psychiatric disease. We predict that these highly integrative explorations of genome organization and function will provide an important alternative to conventional approaches in human brain studies, which mainly are aimed at uncovering group effects by diagnosis but generally face limitations because of cohort size.

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“…The expression of BDNF mRNA and protein is reduced in the dorsolateral prefrontal cortex (PFC) of subjects with schizophrenia (8); another study demonstrated a positive correlation between reduced BDNF mRNA levels and reduced spine density in the same subjects with schizophrenia (58). miR-132 expression is reduced in the PFC from subjects with schizophrenia and in the PFC of adult mice chronically treated during postnatal development with the noncompetitive NMDAR antagonist MK-801 (18). Further experiments will be needed to directly test whether the spine deficits in SR −/− mice are caused by abnormalities in BDNF or miR-132 expression.…”

Section: −/−mentioning

confidence: 99%

“…These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20,21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.…”

mentioning

confidence: 99%

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Balu

Puhl

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

201

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Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

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MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function

Cited by 272 publications

References 45 publications

Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers

Epigenetics in the Human Brain

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

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