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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.

AbstractMicroRNAs (miRNAs) are critical regulators of nervous system function, and in vivo knockout studies have demonstrated that miRNAs are necessary for multiple aspects of neuronal development and survival. However, the role of miRNA biogenesis in the formation and function of synapses in the cerebral cortex is only minimally understood. Here, we have generated and characterized a mouse line with a conditional neuronal deletion of Dgcr8, a miRNA biogenesis protein predicted to process miRNAs exclusively. Loss of Dgcr8 in pyramidal neurons of the cortex results in a non-cell-autonomous reduction in parvalbumin interneurons in the prefrontal cortex, accompanied by a severe deficit in inhibitory synaptic transmission and a corresponding reduction of inhibitory synapses. Together, these results suggest a vital role for miRNAs in governing essential aspects of inhibitory transmission and interneuron development in the mammalian nervous system. These results may be relevant to human diseases such as schizophrenia, where both altered Dgcr8 levels as well as aberrant inhibitory transmission in the prefrontal cortex have been postulated to contribute to the pathophysiology of the disease.

Topics: Interneuron (57%), Prefrontal cortex (57%), Cortex (anatomy) (56%), Cerebral cortex (54%), Nervous system (53%)

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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.
Abstract: The nervous system equips us with capability to adapt to many conditions and circumstances. We rely on an armamentarium of intricately formed neural circuits for many of our adaptive strategies. However, this capability also depends on a well-conserved toolkit of different molecular mechanisms that offer not only compensatory responses to a changing world, but also provide plasticity to achieve changes in cellular state that underlie a broad range of processes from early developmental transitions to life-long memory. Among the molecular tools that mediate changes in cellular state, our understanding of posttranscriptional regulation of gene expression is expanding rapidly. Part of the "epigenetic landscape" that shapes the deployment and robust regulation of gene networks during the construction and the remodeling of the brain is the microRNA system controlling both levels and translation of messenger RNA. Here we consider recent advances in the study of microRNA-mediated regulation of synaptic form and function.

243 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.
Abstract: Loss- and gain-of-function mutations of the X-linked gene MECP2 (methyl-CpG binding protein 2) lead to severe neurodevelopmental disorders in humans, such as Rett syndrome (RTT) and autism. MeCP2 is previously known as a transcriptional repressor by binding to methylated DNA and recruiting histone deacetylase complex (HDAC). Here, we report that MeCP2 regulates gene expression posttranscriptionally by suppressing nuclear microRNA processing. We found that MeCP2 binds directly to DiGeorge syndrome critical region 8 (DGCR8), a critical component of the nuclear microRNA-processing machinery, and interferes with the assembly of Drosha and DGCR8 complex. Protein targets of MeCP2-suppressed microRNAs include CREB, LIMK1, and Pumilio2, which play critical roles in neural development. Gain of function of MeCP2 strongly inhibits dendritic and spine growth, which depends on the interaction of MeCP2 and DGCR8. Thus, control of microRNA processing via direct interaction with DGCR8 represents a mechanism for MeCP2 regulation of gene expression and neural development.

197 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.

142 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.

94 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

75 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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