Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex
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.
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TL;DR: Altered miRNA profiles in biofluids may be potentially useful biomarkers of epileptogenesis and represent an important layer of gene expression control in epilepsy with therapeutic and biomarker potential.
Abstract: Epilepsy is a common, serious neurological disease characterized by recurring seizures. Such abnormal, excessive synchronous firing of neurons arises in part because of imbalances in excitation and inhibition in the brain. The process of epileptogenesis, during which the normal brain is transformed after injury to one capable of generating spontaneous seizures, is associated with large-scale changes in gene expression. These contribute to the remodelling of brain networks that permanently alters excitability. Components of the microRNA (miRNA) biogenesis pathway have been found to be altered in brain tissue from epilepsy patients and experimental epileptogenic insults result in select changes to miRNAs regulating neuronal microstructure, cell death, inflammation, and ion channels. Targeting key miRNAs has been shown to alter brain excitability and suppress or exacerbate seizures, indicating potential for miRNA-based therapeutics in epilepsy. Altered miRNA profiles in biofluids may be potentially useful biomarkers of epileptogenesis. In summary, miRNAs represent an important layer of gene expression control in epilepsy with therapeutic and biomarker potential.
55 citations
TL;DR: A functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes.
Abstract: 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011; Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015; Robin and Shprintzen, J Pediatr 147:90-6, 2005; Schneider et al., Am J Psychiatry 171:627-39, 2014). The mechanistic relationships between heterozygously deleted 22q11.2 genes and 22q11DS phenotypes are still unknown. We assembled a comprehensive “line-up” of the 36 protein coding loci in the 1.5 Mb minimal critical deleted region on hChr22q11.2, plus 20 protein coding loci in the distal 1.5 Mb that defines the 3 Mb typical 22q11DS deletion. We categorized candidates based upon apparent primary cell biological functions. We analyzed 41 of these genes that encode known proteins to determine whether haploinsufficiency of any single 22q11.2 gene—a one gene to one phenotype correspondence due to heterozygous deletion restricted to that locus—versus complex multigenic interactions can account for single or multiple 22q11DS phenotypes. Our 22q11.2 functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes. Shared molecular functions, convergence on fundamental cell biological processes, and related consequences of individual 22q11.2 genes point to a matrix of multigenic interactions due to diminished 22q11.2 gene dosage. These interactions target fundamental cellular mechanisms essential for development, maturation, or homeostasis at subsets of 22q11DS phenotypic sites.
51 citations
TL;DR: The literature on miRNAs and their targets responsible for maladaptive plasticity in chronic pain conditions are reviewed and a retrospective analysis of miRNA expression data published for different pain models is conducted, taking into account recent progress in understanding of the role of mi RNAs in neuronal plasticity.
Abstract: MicroRNAs (miRNAs) are emerging as master regulators of gene expression in the nervous system where they contribute not only to brain development but also to neuronal network homeostasis and plasticity. Their function is the result of a cascade of events including miRNA biogenesis, target recognition, and translation inhibition. It has been suggested that miRNAs are major switches of the genome owing to their ability to regulate multiple genes at the same time. This regulation is essential for normal neuronal activity and, when affected, can lead to drastic pathological conditions. As an example, we illustrate how deregulation of miRNAs can affect neuronal plasticity leading to chronic pain. The origin of pain and its dual role as a key physiological function and a debilitating disease has been highly debated until now. The incidence of chronic pain is estimated to be 20–25% worldwide, thus making it a public health problem. Chronic pain can be considered as a form of maladaptive plasticity. Long-lasting modifications develop as a result of global changes in gene expression, and are thus likely to be controlled by miRNAs. Here, we review the literature on miRNAs and their targets responsible for maladaptive plasticity in chronic pain conditions. In addition, we conduct a retrospective analysis of miRNA expression data published for different pain models, taking into account recent progress in our understanding of the role of miRNAs in neuronal plasticity.
47 citations
Cites background from "Loss of microRNAs in pyramidal neur..."
...The mechanisms involved are not fully understood but it is thought that Ago could compete with eukaryotic translation initiation factor 4 for mRNA-cap binding (Humphreys et al., 2005; Kiriakidou et al., 2007)....
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TL;DR: The mechanisms that regulate microRNA biogenesis are described and the potential to consider microRNAs as putative target for pharmacological intervention, using common psychotropic drugs or more specific tools, with the aim to normalize functions that are disrupted in different psychiatric conditions is discussed.
44 citations
TL;DR: The extent of miRNA regulation at the synapse is revealed and predicted critical microRNAs that would aid future research on the control of neuronal plasticity and etiology of psychiatric diseases are predicted.
Abstract: Differential RNA localization and local protein synthesis regulate synapse function and plasticity in neurons. MicroRNAs are a conserved class of regulatory RNAs that control mRNA stability and translation in tissues. They are abundant in the brain but the extent into which they are involved in synaptic mRNA regulation is poorly known. Herein, a computational analysis of the coding and 3′UTR regions of 242 presynaptic and 304 postsynaptic proteins revealed that 91% of them are predicted to be microRNA targets. Analysis of the longest 3′UTR isoform of synaptic transcripts showed that presynaptic mRNAs have significantly longer 3′UTR than control and postsynaptic mRNAs. In contrast, the shortest 3′UTR isoform of postsynaptic mRNAs is significantly shorter than control and presynaptic mRNAs, indicating they avert microRNA regulation under specific conditions. Examination of microRNA binding site density of synaptic 3′UTRs revealed that they are twice as dense as the rest of protein-coding transcripts and that approximately 50% of synaptic transcripts are predicted to have more than five different microRNA sites. An interaction map exploring the association of microRNAs and their targets revealed that a small set of ten microRNAs is predicted to regulate 77% and 80% of presynaptic and postsynaptic transcripts, respectively. Intriguingly, many of these microRNAs have yet to be identified outside primate mammals, implicating them in cognition differences observed between high-level primates and non-primate mammals. Importantly, the identified miRNAs have been previously associated with psychotic disorders that are characterized by neural circuitry dysfunction, such as schizophrenia. Finally, molecular dissection of their KEGG pathways showed enrichment for neuronal and synaptic processes. Adding on current knowledge, this investigation revealed the extent of miRNA regulation at the synapse and predicted critical microRNAs that would aid future research on the control of neuronal plasticity and etiology of psychiatric diseases.
39 citations
Cites background from "Loss of microRNAs in pyramidal neur..."
...miRNAs have been recognized as essential for neuron development and differentiation on the basis of original research in which the miRNA processing enzymes Dicer or Dgcr8 has been knocked-down [43,44,45]; however, the role they have in homeostasis of mature neurons and, in particular, synaptic function remains poorly understood....
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References
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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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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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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
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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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