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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
TL;DR: In this article, the role of microRNAs in the development of the prefrontal cortex (PFC) in adolescence and individual differences in vulnerability to mental illness was examined, showing that altered levels of microRNA in the PFC are associated with psychopathologies of adolescent onset.

16 citations

Journal ArticleDOI
TL;DR: The role of microRNAs in the development of tolerance following ischemic or epileptic preconditioning and their protective effects have been shown in experimental models of ischemia and epilepsy.
Abstract: Insults to the brain that are sub-threshold for damage activate endogenous protective pathways, which can temporarily protect the brain against a subsequent harmful episode. This mechanism has been named as tolerance and its protective effects have been shown in experimental models of ischemia and epilepsy. The preconditioning-stimulus can be a short period of ischemia or mild seizures induced by low doses of convulsant drugs. Gene-array profiling has shown that both ischemic and epileptic tolerance feature large-scale gene down-regulation but the mechanism are unknown. MicroRNAs are a class of small non-coding RNAs of ~20-22 nucleotides length which regulate gene expression at a post-transcriptional level via mRNA degradation or inhibition of protein translation. MicroRNAs have been shown to be regulated after non-harmful and harmful stimuli in the brain and to contribute to neuroprotective mechanisms. This review focuses on the role of microRNAs in the development of tolerance following ischemic or epileptic preconditioning.

15 citations


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

  • ...Deletion of DGCR8, which affects the production of the precursor microRNA, results in a reduction in brain size and loss of inhibitory synaptic neurotransmission (Babiarz et al., 2011; Hsu et al., 2012)....

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Journal ArticleDOI
TL;DR: Data show that the modality of the presynaptic neuron controls to a large extent the modalities of the postsynaptic neuron, and the exosome and the homeoprotein hypotheses provide novel explanations to add to the well-established earlier mechanism.
Abstract: This paper presents a review of recent work on the role that two epigenetic-related systems may play in information processing mechanisms in the brain. The first consists of exosomes that transport epigenetic-related molecules between neurons. The second consists of homeoproteins like Otx2 that carry information from sense organs to primary sensory cortex. There is developing evidence that presynaptic neurons may be able to modulate the fine microanatomical structure in the postsynaptic neuron. This may be conducted by three mechanisms, of which the first is well established and the latter two are novel. (i) By the well-established activation of receptors that trigger a chain of signalling molecules (second messengers) that result in the upregulation and/or activation of a transcription factor. The two novel systems are the exosome system and homeoproteins. (ii) Exosomes are small vesicles that are released upon activation of the axon terminal, traverse the synaptic cleft, probably via astrocytes and are taken up by the postsynaptic neuron. They carry a load of signalling proteins and a variety of forms of RNA. These loads may then be transported widely throughout the postsynaptic neuron and engineer modulations in the fine structure of computational machinery by epigenetic-related processes. (iii) Otx2 is a transcription factor that, inter alia, controls the development and survival of PV+ GABAergic interneurons (PV cells) in the primary visual cortex. It is synthesized in the retina and is transported to the cortex by a presently unknown mechanism that probably includes direct cell-to-cell transfer, and may, or may not, include transfer by the dynein and exosome systems in addition. These three mechanisms explain a quantity of data from the field of de- and reafferentation plasticity. These data show that the modality of the presynaptic neuron controls to a large extent the modality of the postsynaptic neuron. However, the mechanism that effects this is currently unknown. The exosome and the homeoprotein hypotheses provide novel explanations to add to the well-established earlier mechanism described above.

12 citations

Journal ArticleDOI
TL;DR: The findings suggest that the miRNAs 218a-5p, 219a-4p, and 221-3p regulate vestibular compensation, and target pathway analysis of these mi RNAs supported the results.
Abstract: Unilateral vestibular deafferentation (UVD) interrupts afferent signals from one side, resulting in an imbalance of the resting activity between bilateral vestibular nuclei. Vestibular compensation is the process of balancing the resting activity to reestablish homeostasis. Here, we investigated microRNAs (miRNAs) that regulate vestibular compensation using the Sprague-Dawley rat. After determining the progression of vestibular compensation following UVD, microarray analysis was performed and nine miRNAs were selected as candidates. Following validation by quantitative reverse transcription-PCR, three miRNAs remained. We assessed the effect of these miRNAs on vestibular compensation using miRNA oligomers. We compared the results of the rotarod test and 5-bromo-2'-deoxyuridine immunohistochemistry following UVD between the control group and the groups in which the candidate miRNA oligomers were administered. Administration of miR-218a-5p, 219a-5p, and 221-3p oligomers significantly affected vestibular compensation. Target pathway analysis of these miRNAs supported our results. Our findings suggest that the miRNAs 218a-5p, 219a-5p, and 221-3p regulate vestibular compensation.

11 citations

Journal ArticleDOI
TL;DR: These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants in 22q11.2 deletion syndrome.
Abstract: 22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = −1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

10 citations


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

  • ...Knockout of DGCR8 in pyramidal neurons also resulted in severe microcephaly, cell loss, altered inhibitory synaptic transmission, and premature death (Hsu et al. 2012)....

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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)....

    [...]

  • ...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)....

    [...]

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