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

doi:10.1016/J.MCN.2012.06.002

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

Journal Article•DOI•

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

Ruby Hsu¹, Claude M. Schofield¹, Cassandra G. Dela Cruz¹, Dorothy M. Jones-Davis¹, Robert Blelloch¹, Erik M. Ullian¹ - Show less +2 more•Institutions (1)

University of California, San Francisco¹

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.

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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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Journal Article•DOI•

MicroRNAs Shape the Neuronal Landscape

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Elizabeth M. McNeill¹, David Van Vactor¹•Institutions (1)

Harvard University¹

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.

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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 Article•DOI•

MeCP2 Suppresses Nuclear MicroRNA Processing and Dendritic Growth by Regulating the DGCR8/Drosha Complex

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Tian Lin Cheng¹, Zhizhi Wang², Qiuming Liao¹, Ying Zhu¹, Wenhao Zhou³, Wenqing Xu², Zilong Qiu¹ - Show less +3 more•Institutions (3)

Chinese Academy of Sciences¹, University of Washington², Fudan University³

10 Mar 2014-Developmental Cell

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.

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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 Article•DOI•

Expression of microRNAs and Other Small RNAs in Prefrontal Cortex in Schizophrenia, Bipolar Disorder and Depressed Subjects

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Neil R. Smalheiser¹, Giovanni Lugli¹, Hui Zhang¹, Hooriyah S. Rizavi¹, Edwin H. Cook¹, Yogesh Dwivedi¹ - Show less +2 more•Institutions (1)

University of Illinois at Chicago¹

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.

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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.

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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 Article•DOI•

MicroRNAs and synaptic plasticity--a mutual relationship.

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Ayla Aksoy-Aksel¹, Federico Zampa¹, Gerhard Schratt¹•Institutions (1)

University of Marburg¹

26 Sep 2014-Philosophical Transactions of the Royal Society B

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.

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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.

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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 Article•DOI•

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del

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Dejian Zhao¹, Mingyan Lin¹, Jian Chen¹, Erika Pedrosa¹, Anastasia Hrabovsky¹, H. Matthew Fourcade¹, Deyou Zheng¹, Herbert M. Lachman¹ - Show less +4 more•Institutions (1)

Albert Einstein College of Medicine¹

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.

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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

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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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Journal Article•DOI•

Endogenous brain-derived neurotrophic factor is anterogradely transported in primary sensory neurons

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Xin-Fu Zhou¹, Robert A. Rush¹•Institutions (1)

Flinders University¹

01 Oct 1996-Neuroscience

TL;DR: It is demonstrated that one neurotrophin, brain-derived neurotrophic factor, is transported anterogradely via both peripheral and central processes of spinal sensory neurons, adding a new dimension to the role of neuronal growth factors.

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278 citations

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

...Biosciences), BDNF (1:500, courtesy of Xin-Fu Zhou (Zhou and Rush, 1996)), or actin (1:1000, Sigma) overnight at 4 °C....
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...Proteins were transferred to PVDF membranes (Millipore), blocked in TBS-T, and blotted against TrkB (1:1000, B.D. Biosciences), BDNF (1:500, courtesy of Xin-Fu Zhou (Zhou and Rush, 1996)), or actin (1:1000, Sigma) overnight at 4 °C....
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Journal Article•DOI•

Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression.

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Jie Wu¹, Xiaohui Xie²•Institutions (2)

Boston University¹, Broad Institute²

26 Sep 2006-Genome Biology

TL;DR: It is demonstrated that these different levels of regulation are coordinated through extensive feedbacks, and a network among REST, CREB proteins and the brain-related miRNAs as a robust program for mediating neuronal gene expression is proposed.

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Abstract: Background Two distinct classes of regulators have been implicated in regulating neuronal gene expression and mediating neuronal identity: transcription factors such as REST/NRSF (RE1 silencing transcription factor) and CREB (cAMP response element-binding protein), and microRNAs (miRNAs). How these two classes of regulators act together to mediate neuronal gene expression is unclear.

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250 citations

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

...The reductions of both BDNF and TrkB in the PFC of Dgcr8fl/fl;Cre mice suggests that disrupted signaling through the BDNF/TrkB pathway may be in part responsible for the observed changes in PV expression and inhibitory transmission. miRNAs have been predicted to target BDNF itself; however, brain-specific miRNAs have also been shown to target molecules which regulate BDNF expression, including RE-1 silencing transcription factor (REST) (Conaco et al., 2006; Packer et al., 2008; Wu and Xie, 2006) and methyl CpG-binding protein 2 (MeCP2) (Im et al., 2010; Klein et al., 2007), through homeostatic and doublenegative feedback interactions....
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...…to target molecules which regulate BDNF expression, including RE-1 silencing transcription factor (REST) (Conaco et al., 2006; Packer et al., 2008; Wu and Xie, 2006) and methyl CpG-binding protein 2 (MeCP2) (Im et al., 2010; Klein et al., 2007), through homeostatic and doublenegative feedback…...
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...miRNAs have been predicted to target BDNF itself; however, brain-specific miRNAs have also been shown to target molecules which regulate BDNF expression, including RE-1 silencing transcription factor (REST) (Conaco et al., 2006; Packer et al., 2008; Wu and Xie, 2006) and methyl CpG-binding protein 2 (MeCP2) (Im et al....
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Journal Article•DOI•

Molecular Determinants of Dysregulated GABAergic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia

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Nikolaos Mellios¹, Hsien-Sung Huang¹, Stephen P. Baker¹, Marzena Galdzicka², Edward I. Ginns², Schahram Akbarian¹ - Show less +2 more•Institutions (2)

University of Massachusetts Medical School¹, University of Massachusetts Amherst²

15 Jun 2009-Biological Psychiatry

TL;DR: Prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.

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239 citations

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

...Decreases in PV interneurons in the PFC specifically have been described in schizophrenia (Blum and Mann, 2002; Mellios et al., 2009; Zhang and Reynolds, 2002), while changes in miRNA expression patterns have been reported in schizophrenia postmortem studies (Beveridge et al....
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...Decreases in PV interneurons in the PFC specifically have been described in schizophrenia (Blum and Mann, 2002; Mellios et al., 2009; Zhang and Reynolds, 2002), while changes in miRNA expression patterns have been reported in schizophrenia postmortem studies (Beveridge et al., 2008; Perkins et al.,…...
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Journal Article•DOI•

Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system

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Yoko Kawase-Koga¹, Gaizka Otaegi¹, Tao Sun¹•Institutions (1)

Cornell University¹

01 Nov 2009-Developmental Dynamics

TL;DR: It is shown that specifically deleting Dicer expression in the CNS and in the cerebral cortex using two Cre lines results in reduced progenitor numbers, abnormal neuronal differentiation, and thinner cortical wall.

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Abstract: MicroRNAs, processed by the RNAase III enzyme Dicer, are approximately 22 nucleotide endogenous noncoding small RNAs. The function of Dicer in the mouse central nervous system (CNS) development is not well understood. Here, we show that specifically deleting Dicer expression in the CNS and in the cerebral cortex using two Cre lines results in reduced progenitor numbers, abnormal neuronal differentiation, and thinner cortical wall. Incomplete Dicer deletion during early embryonic stages contributes to normal development of early-born neurons in the cortex and motor neurons in the spinal cord. However, at late embryonic stages when Dicer is completely ablated in the CNS, the migration of late-born neurons in the cortex and oligodendrocyte precursor expansion and differentiation in the spinal cord are greatly affected. Our studies of different timings of Dicer deletion demonstrate the importance of the Dicer-mediated microRNA pathway in regulating distinct phases of neurogenesis and gliogenesis during the CNS development.

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230 citations

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

..., 2009); however, we did not observe the grossly disrupted lamination which has consistently been reported across multiple conditional Dicer strains (De Pietri Tonelli et al., 2008; Kawase-Koga et al., 2009), suggesting that miRNA-independent pathways may underlie this component of the Dicer phenotype....
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...…however, we did not observe the grossly disrupted lamination which has consistently been reported across multiple conditional Dicer strains (De Pietri Tonelli et al., 2008; Kawase-Koga et al., 2009), suggesting that miRNA-independent pathways may underlie this component of the Dicer phenotype....
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Journal Article•DOI•

GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum.

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Chi-Sung Chiu¹, Stephen G. Brickley, Kimmo Jensen, Amber L. Southwell, Sheri McKinney, Stuart G. Cull-Candy, Istvan Mody, Henry A. Lester - Show less +4 more•Institutions (1)

California Institute of Technology¹

23 Mar 2005-The Journal of Neuroscience

TL;DR: The excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

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Abstract: GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABAA receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABAA-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

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215 citations

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

...Common forms of ataxia, seizures, and tremors are predicted to be primarily GABAergic in origin (Chiu et al., 2005)....
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...Reduced inhibitory postsynaptic currents at Dgcr8fl/fl;Cre pyramidal neurons Common forms of ataxia, seizures, and tremors are predicted to be primarily GABAergic in origin (Chiu et al., 2005)....
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