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Journal ArticleDOI

Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex

01 Jul 2012-Molecular and Cellular Neuroscience (Mol Cell Neurosci)-Vol. 50, Iss: 3, pp 283-292
TL;DR: A vital role for miRNAs in governing essential aspects of inhibitory transmission and interneuron development in the mammalian nervous system is suggested.
About: This article is published in Molecular and Cellular Neuroscience.The article was published on 2012-07-01 and is currently open access. It has received 51 citations till now. The article focuses on the topics: Interneuron & Prefrontal cortex.
Citations
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Journal ArticleDOI
09 Aug 2012-Neuron
TL;DR: Here it is considered that recent advances in the study of microRNA-mediated regulation of synaptic form and function in mice are considered to be significant.

263 citations


Cites background from "Loss of microRNAs in pyramidal neur..."

  • ...This research directly implicates miRNAs as functioning in inhibitory synapses and illustrates the global effects cellspecific knockdown of miRNAs can impart (Hsu et al., 2012)....

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Journal ArticleDOI
TL;DR: It is reported that MeCP2 regulates gene expression posttranscriptionally by suppressing nuclear microRNA processing by binding directly to DiGeorge syndrome critical region 8 (DGCR8), a critical component of the nuclear micro RNA-processing machinery, and interferes with the assembly of Drosha and DG CR8 complex.

220 citations


Cites background from "Loss of microRNAs in pyramidal neur..."

  • ...It is important that nuclear miRNA processing is critical for proper synaptic function as shown by Ullian and colleagues that deletion of DGCR8 leads to defects of inhibitory synaptic transmission (Hsu et al., 2012)....

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Journal ArticleDOI
27 Jan 2014-PLOS ONE
TL;DR: 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, suggesting some deficit in miRNA biogenesis, transport, processing or turnover in schizophrenia that is selective for the synaptic compartment.
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.

165 citations


Cites background from "Loss of microRNAs in pyramidal neur..."

  • ...In this context, it is interesting that down-regulating miRNAs selectively in excitatory neurons, in mouse forebrain, produces discrete deficits in shortterm plasticity and inhibitory neurotransmission that are reminiscent in some ways of a schizophrenia phenotype [30,31]....

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Journal ArticleDOI
TL;DR: How neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals is summarized.
Abstract: MicroRNAs (miRNAs) are rapidly emerging as central regulators of gene expression in the postnatal mammalian brain. Initial studies mostly focused on the function of specific miRNAs during the development of neuronal connectivity in culture, using classical gain- and loss-of-function approaches. More recently, first examples have documented important roles of miRNAs in plastic processes in intact neural circuits in the rodent brain related to higher cognitive abilities and neuropsychiatric disease. At the same time, evidence is accumulating that miRNA function itself is subjected to sophisticated control mechanisms engaged by the activity of neural circuits. In this review, we attempt to pay tribute to this mutual relationship between miRNAs and synaptic plasticity. In particular, in the first part, we summarize how neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals. In the second part, we discuss recent examples of miRNA function in synaptic plasticity in rodent models and their implications for higher cognitive function and neurological disorders, with a special emphasis on epilepsy as a disorder of abnormal nerve cell activity.

106 citations


Cites background from "Loss of microRNAs in pyramidal neur..."

  • ...Although the gross anatomical features are retained, reduction in dendritic complexity, alteration in spine size and density [72] as well as selective decrease in inhibitory network [73] and deficient adult neurogenesis [74] has been reported in relation to monoallelic DGCR8 knockdown....

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Journal ArticleDOI
14 Jul 2015-PLOS ONE
TL;DR: Differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.
Abstract: We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q112 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q112 del Using thresholds of p<001 for nominal significance and 15-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher) Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<005), including 4 miRNAs that map to the 22q112 del region In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q112 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (eg, miR-34, miR-4449, miR-146b-3p, and miR-23a-5p) Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs Our findings suggest that: i neurons with 22q112 del recapitulate the miRNA expression patterns expected of 22q112 haploinsufficiency, ii differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis

89 citations


Cites background from "Loss of microRNAs in pyramidal neur..."

  • ...In addition, Dgcr8 knockout mice have deficits in the development of excitatory synapses and a reduction of parvalbumin interneurons in the prefrontal cortex [2,48]....

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References
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations


"Loss of microRNAs in pyramidal neur..." refers background in this paper

  • ...MicroRNAs (miRNAs) constitute a class of highly-conserved, ~22- 24 nucleotide (nt) long non-coding RNAs that bind to the 3’ untranslated region of target mRNA species, leading to translational repression or mRNA degradation (reviewed in Bartel, 2004)....

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  • ...For instance, endo-siRNAs processed by Dicer typically result in target degradation, whereas Dgcr8derived miRNAs more commonly act via translational repression (Ambros, 2004; Bartel, 2004)....

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Journal ArticleDOI
TL;DR: This study enters into the particular topics of the relative quantification in real-time RT-PCR of a target gene transcript in comparison to a reference gene transcript and presents a new mathematical model that needs no calibration curve.
Abstract: Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform, provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters into the particular topics of the relative quantification in real-time RT–PCR of a target gene transcript in comparison to a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler PCR using the established mathematical model.

30,462 citations


"Loss of microRNAs in pyramidal neur..." refers methods in this paper

  • ...All qPCR reactions were performed in triplicate and relative quantifications were calculated using the Pfaffl method (Pfaffl, 2001)....

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Journal ArticleDOI
15 Sep 2004-Nature
TL;DR: Evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
Abstract: MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

9,986 citations

Journal ArticleDOI
TL;DR: It was found that the development of motor seizures by stimulation of the amygdala resulted in an increased ability of the contralateral amygdala, and the septal area, but not of the hippocampus, to drive motor seizures when stimulated (“transfer”).

6,638 citations


"Loss of microRNAs in pyramidal neur..." refers methods in this paper

  • ...Mice were observed for at least 30 minutes after pilocarpine injection, and seizures were quantified by using the classification of Racine (1972)....

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Journal ArticleDOI
TL;DR: This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
Abstract: Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.

2,854 citations