scholarly journals The organization and developmental establishment of cortical interneuron presynaptic circuits

2020 ◽  
Author(s):  
Gabrielle Pouchelon ◽  
Yannick Bollmann ◽  
Elaine Fisher ◽  
Chimuanya K Agba ◽  
Qing Xu ◽  
...  
Keyword(s):  
Fragile X ◽  
Inhibitory Interneurons ◽  
Loss Of Function ◽  
Cortical Circuits ◽  
Cell Type ◽  
Cortical Interneuron ◽  
First Order ◽  
Cortical Areas ◽  
Cell Type Specific ◽  
Do So

Sensory and cognitive functions are processed in discrete cortical areas and depend upon the integration of long range cortical and subcortical inputs. PV and SST inhibitory interneurons (cINs) gate these inputs and failure to do so properly is implicated in many neurodevelopmental disorders. The logic by which these interneuron populations are integrated into cortical circuits and how these vary across sensory versus associative cortical areas is unknown. To answer this question, we began by surveying the breadth of afferents impinging upon PV and SST cINs within distinct cortical areas. We found that presynaptic inputs to both cIN populations are similar and primarily dictated by their areal location. By contrast, the timing of when they receive these afferents is cell-type specific. In sensory regions, both SST and PV cINs initially receive thalamocortical first order inputs. While by adulthood PV cINs remain heavily skewed towards first order inputs, SST cINs receive an equal balance of first and higher order thalamic afferents. Remarkably, while perturbations to sensory experience affect PV cIN thalamocortical connectivity, SST cIN connectivity is disrupted in a model of fragile X syndrome (Fmr1 loss of function) but not a model of ASD (Shank3B loss of function). Altogether, these data provide a comprehensive map of cIN afferents within different functional cortical areas and reveal the region-specific logic by which PV and SST cIN circuits are established.

scholarly journals PlexinA4-Semaphorin3A mediated crosstalk between main cortical interneuron classes is required for superficial interneurons lamination

2020 ◽  
Author(s):  
Greta Limoni ◽  
Mathieu Niquille ◽  
Sahana Murthy ◽  
Denis Jabaudon ◽  
Alexandre Dayer
Keyword(s):  
Cerebral Cortex ◽  
Serotonin Receptor ◽  
Deep Layer ◽  
Cortical Plate ◽  
Inhibitory Interneurons ◽  
Cell Type ◽  
Cortical Layers ◽  
Cortical Interneuron ◽  
Cell Type Specific ◽  
Genetic Deletion

SummaryIn the mammalian cerebral cortex, the developmental events governing the allocation of different classes of inhibitory interneurons (INs) into distinct cortical layers are poorly understood. Here we report that the guidance receptor PlexinA4 (PLXNA4) is upregulated in serotonin receptor 3a-expressing (HTR3A+) cortical INs (hINs) as they invade the cortical plate and that it regulates their laminar allocation to superficial cortical layers. We find that the PLXNA4 ligand Semaphorin3A (SEMA3A) acts as a chemorepulsive factor on hINs migrating into the nascent cortex and demonstrate that SEMA3A specifically controls their laminar positioning through PLXNA4. We identify that deep layer INs constitute a major source of SEMA3A in the developing cortex and demonstrate that cell-type specific genetic deletion of SEMA3A in these INs specifically affects the laminar allocation of hINs. These data demonstrate that in the neocortex, deep layer INs control the laminar allocation of hINs into superficial layers.

scholarly journals Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function

2021 ◽  
Author(s):  
Alexei M. Bygrave ◽  
Ayesha Sengupta ◽  
Ella P. Jackert ◽  
Mehroz Ahmed ◽  
Beloved Adenuga ◽  
...  
Keyword(s):  
Inhibitory Interneuron ◽  
Nmda Receptor Antagonist ◽  
Specific Protein ◽  
Network Activity ◽  
Scaffolding Protein ◽  
Inhibitory Interneurons ◽  
Cell Type ◽  
Cell Type Specific

Synapses in the brain exhibit cell–type–specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell–type–specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron–specific synapse–enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd–95. Intriguingly, we show that Btbd11 can undergo liquid–liquid phase separation when expressed with Psd–95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin–positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell–type–specific protein that supports glutamatergic synapse function in inhibitory interneurons–with implication for circuit function and animal behavior.

scholarly journals Zebrafish Cre/lox regulated UFlip alleles generated by CRISPR/Cas targeted integration provide cell-type specific conditional gene inactivation

2021 ◽  
Author(s):  
Maira P. Almeida ◽  
Sekhar Kambakam ◽  
Fang Liu ◽  
Zhitao Ming ◽  
Jordan M. Welker ◽  
...  
Keyword(s):  
Gene Function ◽  
Cre Recombinase ◽  
Gene Trap ◽  
Gene Inactivation ◽  
Loss Of Function ◽  
Cell Type ◽  
Active Gene ◽  
Indel Mutation ◽  
Targeted Integration ◽  
Cell Type Specific

The ability to regulate gene activity spatially and temporally is essential to investigate cell type specific gene function during development and in postembryonic processes and disease models. The Cre/lox system has been widely used for performing cell and tissue-specific conditional analysis of gene function in zebrafish, but simple and efficient methods for isolation of stable, Cre/lox regulated alleles are lacking. Here we applied our GeneWeld CRISPR/Cas9 short homology-directed targeted integration strategy to generate floxed conditional alleles that provide robust gene knockdown and strong loss of function phenotypes. A universal targeting vector, UFlip, with sites for cloning short 24-48 bp homology arms flanking a floxed mRFP gene trap plus secondary reporter cassette, was integrated into an intron in hdac1, rbbp4, and rb1. Active, gene off orientation hdac1-UFlip-Off and rb1-UFlip-Off integration alleles result in >99% reduction of gene expression in homozygotes and recapitulate known indel loss of function phenotypes. Passive, gene on orientation rbbp4-UFlip-On and rb1-UFlip-On integration alleles do not cause phenotypes in trans-heterozygous combination with an indel mutation. Cre recombinase injection leads to recombination at alternating pairs of loxP and lox2272 sites, inverting and locking the cassette into the active, gene off orientation, and the expected mutant phenotypes. In combination with our endogenous neural progenitor Cre drivers we demonstrate rbbp4-UFlip-On and rb1-UFlip-On gene inactivation phenotypes can be restricted to specific neural cell populations. Replacement of the UFlip mRFP primary reporter gene trap with a 2A-RFP in rbbp4-UFlip-Off, or 2A-KalTA4 in rb1-UFlip-Off, shows strong RFP expression in wild type or UAS:RFP injected embryos, respectively. Together these results validate a simplified approach for efficient isolation of highly mutagenic Cre/lox responsive conditional gene alleles to advance zebrafish Cre recombinase genetics.

scholarly journals Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins against human alloreactive T-cell clones

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2445-2454 ◽  
Author(s):  
FM Uckun ◽  
DE Myers ◽  
JA Ledbetter ◽  
SL Wee ◽  
DA Vallera
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Target Cells ◽  
Cell Type ◽  
T Cell Clones ◽  
First Order ◽  
Cell Clones ◽  
T Cell Clone ◽  
Cell Type Specific ◽  
Alloreactive T Cell

Abstract Potent T-cell subset-directed immunotoxins (ITs) were generated by conjugating the anti-CD4 monoclonal antibody (MoAb) G17–2 and the anti- CD8 MoAb G10.1 to the ribosome-inhibitory protein, ricin. The cell-type- specific cytotoxicities of the generated ITs were evaluated at the clonal level using human alloreactive T-cell clones. The kinetics of anti-CD4 ricin-induced inactivation of protein synthesis in target CD4+ cloned T-cells was first order with no detectable lag period and a maximum rate of 0.07 logs per hour (t10 = 13.6 hours; first-order rate constant/K = 0.17 hr-1). The alloantigen specific lytic function of the CD4+ cytolytic T-cell clone JMAC28 was acutely sensitive to anti-CD4 ricin, and no residual lytic activity against allogeneic targets was detectable 24 hours after treatment with as little as 0.5 mmol/L anti- CD4 ricin. Notably, both anti-CD4 ricin and anti-CD8 ricin elicited a selective and dose-dependent inhibition of clonal proliferation of target T-cell clones with a maximum kill of greater than 3 logs at 5 nmol/L. No significant “bystander effects” were observed for non-target cells. Bone marrow progenitor cells CFU-GM, BFU-E, and CFU-GEMM were only minimally affected by either IT. We conclude that these ITs show considerable potential for effective depletion of T-cell subpopulations from allogeneic donor marrow grafts for clinical graft-versus-host disease (GVHD) prophylaxis.

scholarly journals Genetic Disruption of Cortical Interneuron Development Causes Region- and GABA Cell Type-Specific Deficits, Epilepsy, and Behavioral Dysfunction

2003 ◽  
Vol 23 (2) ◽  
pp. 622-631 ◽  
Author(s):  
Elizabeth M. Powell ◽  
Daniel B. Campbell ◽  
Gregg D. Stanwood ◽  
Caleb Davis ◽  
Jeffrey L. Noebels ◽  
...  
Keyword(s):  
Cell Type ◽  
Cortical Interneuron ◽  
Behavioral Dysfunction ◽  
Cell Type Specific ◽  
Interneuron Development

scholarly journals Mouse hue and wavelength-specific luminance contrast sensitivity are non-uniform across visual space

2017 ◽  
Author(s):  
Daniel J. Denman ◽  
Jennifer A. Luviano ◽  
Douglas R. Ollerenshaw ◽  
Sissy Cross ◽  
Derric Williams ◽  
...  
Keyword(s):  
Contrast Sensitivity ◽  
Visual Space ◽  
Luminance Contrast ◽  
Neural Systems ◽  
Cell Type ◽  
Cone Opsin ◽  
Visual Behaviors ◽  
Cell Type Specific ◽  
Cone Opsins ◽  
Do So

AbstractMammalian visual behaviors, as well as responses in the neural systems thought to underlie these behaviors, are driven by luminance and hue contrast. With tools for measuring activity in cell-type specific populations in the mouse during visual behavior gaining traction, it is important to define the extent of luminance and hue information that is behaviorally-accessible to the mouse. A non-uniform distribution of cone opsins in the mouse potentially complicates both luminance and hue sensitivity: opposing gradients of short (UV-shifted) and middle (blue/green) cone opsins suggest that hue discrimination and wavelength-specific luminance contrast sensitivity may differ depending on retinotopic location. Here we ask if, and how well, mice can discriminate color and wavelength-specific luminance across visuotopic space. We found that mice were able to discriminate hue, and were able to do so more broadly across visuotopic space than expected from the cone-opsin distribution. We also found wavelength-band specific differences in luminance sensitivity.

Role of SGP2, a suppressor of a gpa1 mutation, in the mating-factor signaling pathway of Saccharomyces cerevisiae

1988 ◽  
Vol 8 (12) ◽  
pp. 5410-5416
Author(s):  
N Nakayama ◽  
K Arai ◽  
K Matsumoto
Keyword(s):  
Signaling Pathway ◽  
Growth Defect ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Ras Proteins ◽  
Cell Type ◽  
Guanine Nucleotide Binding Protein ◽  
Cell Type Specific ◽  
Guanine Nucleotide Binding ◽  
Mating Factor

Loss of function of GPA1, which encodes a guanine-nucleotide-binding protein, arrests the cell at the G1 phase and allows it to mate, suggesting that the gpa1 mutation spontaneously exerts an intracellular signal that mimics the action of mating factor. We have cloned the SGP2 gene, which was first identified as a secondary mutation that allowed a gpa1::HIS3 mutant to grow and to show a non-cell-type-specific sterile phenotype. Disruption of SGP2 confers temperature-sensitive growth and a-specific sterile phenotypes, characteristics similar to those conferred by the dpr1 (ram) mutation, a suppressor of RAS2Val-19. The following observations indicate that SGP2 and DPR1 are in fact identical. (i) The cloned SGP2 complements both the temperature-sensitive growth and the a-specific sterility of the dpr1 mutant and can be integrated into the chromosomal DPR1 locus. (ii) The cloned DPR1, in turn, complements the ability of sgp2 to suppress the lethality of gpa1::HIS3. (iii) The dpr1 mutation suppresses the growth defect of gpa1::HIS3, and the dpr1 gpa1::HIS3 strain shows a non-cell-type-specific sterile phenotype. (iv) sgp2 is closely linked to the dpr1 locus. The DPR1 product has been shown to be responsible for processing and fatty acid acylation of a-factor and RAS proteins at their carboxyl termini. Therefore, the SGP2 (DPR1) product may be involved in membrane localization of an essential component in the mating-factor signaling pathway.

scholarly journals Role of SGP2, a suppressor of a gpa1 mutation, in the mating-factor signaling pathway of Saccharomyces cerevisiae.

1988 ◽  
Vol 8 (12) ◽  
pp. 5410-5416 ◽  
Author(s):  
N Nakayama ◽  
K Arai ◽  
K Matsumoto
Keyword(s):  
Signaling Pathway ◽  
Growth Defect ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Ras Proteins ◽  
Cell Type ◽  
Guanine Nucleotide Binding Protein ◽  
Cell Type Specific ◽  
Guanine Nucleotide Binding ◽  
Mating Factor

Loss of function of GPA1, which encodes a guanine-nucleotide-binding protein, arrests the cell at the G1 phase and allows it to mate, suggesting that the gpa1 mutation spontaneously exerts an intracellular signal that mimics the action of mating factor. We have cloned the SGP2 gene, which was first identified as a secondary mutation that allowed a gpa1::HIS3 mutant to grow and to show a non-cell-type-specific sterile phenotype. Disruption of SGP2 confers temperature-sensitive growth and a-specific sterile phenotypes, characteristics similar to those conferred by the dpr1 (ram) mutation, a suppressor of RAS2Val-19. The following observations indicate that SGP2 and DPR1 are in fact identical. (i) The cloned SGP2 complements both the temperature-sensitive growth and the a-specific sterility of the dpr1 mutant and can be integrated into the chromosomal DPR1 locus. (ii) The cloned DPR1, in turn, complements the ability of sgp2 to suppress the lethality of gpa1::HIS3. (iii) The dpr1 mutation suppresses the growth defect of gpa1::HIS3, and the dpr1 gpa1::HIS3 strain shows a non-cell-type-specific sterile phenotype. (iv) sgp2 is closely linked to the dpr1 locus. The DPR1 product has been shown to be responsible for processing and fatty acid acylation of a-factor and RAS proteins at their carboxyl termini. Therefore, the SGP2 (DPR1) product may be involved in membrane localization of an essential component in the mating-factor signaling pathway.

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