Abstract:
:Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS. :Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21. Affected individuals show delayed growth, characteristic facial features, altered brain development; with mild to severe intellectual disability. The exact mechanisms underlying the intellectual disability in Down syndrome are unclear, although studies in mice have provided clues. Drugs that reduce the inhibitory activity in the brain improve cognition in a mouse model of Down syndrome. This suggests that excessive inhibitory activity may contribute to the cognitive impairments. Many different neural circuits generate inhibitory activity in the brain. These circuits contain cells called interneurons. Sub-types of interneurons act via different mechanisms to reduce the activity of neurons. Identifying the interneurons that are affected in Down syndrome would thus improve our understanding of the brain basis of the disorder. Zorrilla de San Martin et al. compared mice with Down syndrome to unaffected control mice. The results revealed an increased activity in two types of inhibitory brain circuits in Down syndrome. The first contains interneurons called Martinotti cells. These help the brain to combine inputs from different sources. The second contains interneurons called parvalbumin-positive basket cells. These help different areas of the brain to synchronize their activity, which in turn makes it easier for those areas to exchange information. By mapping the changes in inhibitory circuits in Down syndrome, Zorrilla de San Martin et al. have provided new insights into the biological basis of the disorder. Future studies should examine whether targeting specific circuits with pharmacological treatments could ultimately help reduce the associated impairments.
journal_name
Elifejournal_title
eLifeauthors
Zorrilla de San Martin J,Donato C,Peixoto J,Aguirre A,Choudhary V,De Stasi AM,Lourenço J,Potier MC,Bacci Adoi
10.7554/eLife.58731subject
Has Abstractpub_date
2020-08-12 00:00:00issn
2050-084Xpii
58731journal_volume
9pub_type
杂志文章相关文献
eLife文献大全abstract::Migration of skeletal muscle precursor cells is a key step during limb muscle development and depends on the activity of PAX3 and MET. Here, we demonstrate that BRAF serves a crucial function in formation of limb skeletal muscles during mouse embryogenesis downstream of MET and acts as a potent inducer of myoblast cel...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.18351
更新日期:2016-12-01 00:00:00
abstract::Experience-dependent reorganisation of functional maps in the cerebral cortex is well described in the primary sensory cortices. However, there is relatively little evidence for such cortical reorganisation over the short-term. Using human somatosensory cortex as a model, we investigated the effects of a 24 hr gluing ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.17280
更新日期:2016-12-30 00:00:00
abstract::Nerve tissue contains a high density of chemical synapses, about 1 per µm3 in the mammalian cerebral cortex. Thus, even for small blocks of nerve tissue, dense connectomic mapping requires the identification of millions to billions of synapses. While the focus of connectomic data analysis has been on neurite reconstru...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.26414
更新日期:2017-07-14 00:00:00
abstract::The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.36828
更新日期:2018-07-16 00:00:00
abstract::Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mou...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.15614
更新日期:2016-09-13 00:00:00
abstract::Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution i...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.28652
更新日期:2017-09-26 00:00:00
abstract::Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial surface, the importance of this localization is unclear. As yeast switch to respiratory metabolism, there is an increase in...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.57814
更新日期:2020-08-07 00:00:00
abstract::Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a ph...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.59614
更新日期:2020-10-06 00:00:00
abstract::Sex-optimal diets have different effects on gene expression in female and male flies. ...
journal_title:eLife
pub_type: 评论,杂志文章
doi:10.7554/eLife.51289
更新日期:2019-10-01 00:00:00
abstract::Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that degrades aberrant mRNAs and also regulates the expression of a wide range of physiological transcripts. RUVBL1 and RUVBL2 AAA-ATPases form an hetero-hexameric ring that is part of several macromolecular complexes such as INO80, SWR1, and R2TP. Interesti...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.63042
更新日期:2020-11-18 00:00:00
abstract::Deinococcus radiodurans (DR) survives in the presence of hundreds of double-stranded DNA (dsDNA) breaks by efficiently repairing such breaks. RecO, a protein that is essential for the extreme radioresistance of DR, is one of the major recombination mediator proteins in the RecA-loading process in the RecFOR pathway. H...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.50945
更新日期:2020-04-16 00:00:00
abstract::Shade avoidance syndrome enables shaded plants to grow and compete effectively against their neighbors. In Arabidopsis, the shade-induced de-phosphorylation of the transcription factor PIF7 (PHYTOCHROME-INTERACTING FACTOR 7) is the key event linking light perception to stem elongation. However, the mechanism through w...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.31636
更新日期:2018-06-21 00:00:00
abstract::Smoothened (Smo) inhibition by Patched (Ptch) is central to Hedgehog (Hh) signaling. Ptch, a proton driven antiporter, is required for Smo inhibition via an unknown mechanism. Hh ligand binding to Ptch reverses this inhibition and activated Smo initiates the Hh response. To determine whether Ptch inhibits Smo strictly...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.17634
更新日期:2016-08-23 00:00:00
abstract::Termination of messenger RNA translation in Bacteria and Archaea is initiated by release factors (RFs) 1 or 2 recognizing a stop codon in the ribosomal A site and releasing the peptide from the P-site transfer RNA. After release, RF-dissociation is facilitated by the G-protein RF3. Structures of ribosomal complexes wi...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.00411
更新日期:2013-06-04 00:00:00
abstract::Ten countries have reported pfhrp2/pfhrp3 gene deletions since the first observation of pfhrp2-deleted parasites in 2012. In a previous study (Watson et al., 2017), we characterised the drivers selecting for pfhrp2/3 deletions and mapped the regions in Africa with the greatest selection pressure. In February 2018, the...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.40339
更新日期:2019-05-02 00:00:00
abstract::Burkholderia thailandensis uses acyl-homoserine lactone-mediated quorum sensing systems to regulate hundreds of genes. Here we show that cell-cell contact-dependent type VI secretion (T6S) toxin-immunity systems are among those activated by quorum sensing in B. thailandensis. We also demonstrate that T6S is required t...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.14712
更新日期:2016-05-16 00:00:00
abstract::Accurate chromosome segregation relies on bioriented amphitelic attachments of chromosomes to microtubules of the mitotic spindle, in which sister chromatids are connected to opposite spindle poles. BUB-1 is a protein of the Spindle Assembly Checkpoint (SAC) that coordinates chromosome attachment with anaphase onset. ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.40690
更新日期:2018-12-14 00:00:00
abstract::Apical secretion from epithelial tubes of the Drosophila embryo is mediated by apical F-actin cables generated by the formin-family protein Diaphanous (Dia). Apical localization and activity of Dia are at the core of restricting F-actin formation to the correct membrane domain. Here we identify the mechanisms that tar...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.00666
更新日期:2013-07-09 00:00:00
abstract::Pancreatic ATP-sensitive K+ channels (KATP) comprise four inward rectifier subunits (Kir6.2), each associated with a sulphonylurea receptor (SUR1). ATP/ADP binding to Kir6.2 shuts KATP. Mg-nucleotide binding to SUR1 stimulates KATP. In the absence of Mg2+, SUR1 increases the apparent affinity for nucleotide inhibition...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.52775
更新日期:2020-01-07 00:00:00
abstract::Although seasonality is widespread and can cause fluctuations in the intensity and direction of natural selection, we have little information about the consequences of seasonal fitness trade-offs for population dynamics. Here we exposed populations of Drosophila melanogaster to repeated seasonal changes in resources a...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.18770
更新日期:2017-02-06 00:00:00
abstract::Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulato...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.51188
更新日期:2020-02-17 00:00:00
abstract::The eukaryotic replisome assembles around the CMG helicase, which stably associates with DNA replication forks throughout elongation. When replication terminates, CMG is ubiquitylated on its Mcm7 subunit and disassembled by the Cdc48/p97 ATPase. Until now, the regulation that restricts CMG ubiquitylation to terminatio...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.60371
更新日期:2020-08-17 00:00:00
abstract::Intergroup conflict contributes to human discrimination and violence, but persists because individuals make costly contributions to their group's fighting capacity. Yet, how group members effectively coordinate their contributions during intergroup conflict remains poorly understood. Here, we examine the role of oxyto...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.40698
更新日期:2019-01-25 00:00:00
abstract::Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and pr...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.57028
更新日期:2020-06-08 00:00:00
abstract::Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host's immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.55692
更新日期:2020-05-04 00:00:00
abstract::Rod and cone photoreceptors are highly similar in many respects but they have important functional and molecular differences. Here, we investigate genome-wide patterns of DNA methylation and chromatin accessibility in mouse rods and cones and correlate differences in these features with gene expression, histone marks,...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.11613
更新日期:2016-03-07 00:00:00
abstract::The mammalian auditory sensory epithelium has one of the most stereotyped cellular patterns known in vertebrates. Mechano-sensory hair cells are arranged in precise rows, with one row of inner and three rows of outer hair cells spanning the length of the spiral-shaped sensory epithelium. Aiding such precise cellular p...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.47613
更新日期:2019-06-12 00:00:00
abstract::During cell locomotion and endocytosis, membrane-tethered WASP proteins stimulate actin filament nucleation by the Arp2/3 complex. This process generates highly branched arrays of filaments that grow toward the membrane to which they are tethered, a conflict that seemingly would restrict filament growth. Using three-c...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.01008
更新日期:2013-09-03 00:00:00
abstract::Cells respond to protein misfolding and aggregation in the cytosol by adjusting gene transcription and a number of post-transcriptional processes. In parallel to functional reactions, cellular structure changes as well; however, the mechanisms underlying the early adaptation of cellular compartments to cytosolic prote...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.29388
更新日期:2017-11-01 00:00:00
abstract::Yeast cells undergoing the diauxic response show a striking upstream shift in poly(A) site utilization, with increased use of ORF-proximal poly(A) sites resulting in shorter 3' mRNA isoforms for most genes. This altered poly(A) pattern is extremely similar to that observed in cells containing Pol II derivatives with s...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.59810
更新日期:2020-08-26 00:00:00