19,860 research outputs found
Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders
No full textAbstractImbalances between excitation and inhibition in synaptic transmission and neural circuits have been implicated in autism spectrum disorders. Excitation and inhibition imbalances are frequently observed in animal models of autism spectrum disorders, and their correction normalizes key autistic-like phenotypes in these animals. These results suggest that excitation and inhibition imbalances may contribute to the development and maintenance of autism spectrum disorders and represent an important therapeutic target
Gene Dosage- and Age-Dependent Differential Transcriptomic Changes in the Prefrontal Cortex of Shank2-Mutant Mice
No full textShank2 is an abundant postsynaptic scaffolding protein that is known to regulate excitatory synapse assembly and synaptic transmission and has been implicated in various neurodevelopmental disorders, including autism spectrum disorders (ASD). Previous studies on Shank2-mutant mice provided mechanistic insights into their autistic-like phenotypes, but it remains unclear how transcriptomic patterns are changed in brain regions of the mutant mice in age- and gene dosage-dependent manners. To this end, we performed RNA-Seq analyses of the transcripts from the prefrontal cortex (PFC) of heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile (week 3) and adult (week 12) stages. Juvenile heterozygous Shank2-mutant mice showed upregulation of glutamate synapse-related genes, downregulation of ribosomal and mitochondrial genes, and transcriptomic changes that are opposite to those observed in ASD (anti-ASD) such as upregulation of ASD_down (downregulated in ASD), GABA neuron-related, and oligodendrocyte-related genes. Juvenile homozygous Shank2 mice showed upregulation of chromatin-related genes and transcriptomic changes that are in line with those occurring in ASD (pro-ASD) such as downregulation of ASD_down, GABA neuron-related, and oligodendrocyte-related genes. Adult heterozygous and homozygous Shank2-mutant mice both exhibited downregulation of ribosomal and mitochondrial genes and pro-ASD transcriptomic changes. Therefore, the gene dosage- and age-dependent effects of Shank2 deletions in mice include differential transcriptomic changes across distinct functional contexts, including synapses, chromatin, ribosomes, mitochondria, GABA neurons, and oligodendrocytes.11Nsciescopu
Shank2 Deletion in Parvalbumin Neurons Leads to Moderate Hyperactivity, Enhanced Self-Grooming and Suppressed Seizure Susceptibility in Mice
No full textShank2 is an abundant postsynaptic scaffolding protein implicated in neurodevelopmental and psychiatric disorders, including autism spectrum disorders (ASD). Deletion of Shank2 in mice has been shown to induce social deficits, repetitive behaviors, and hyperactivity, but the identity of the cell types that contribute to these phenotypes has remained unclear. Here, we report a conditional mouse line with a Shank2 deletion restricted to parvalbumin (PV)-positive neurons (Pv-Cre;Shank2fl/fl mice). These mice display moderate hyperactivity in both novel and familiar environments and enhanced self-grooming in novel, but not familiar, environments. In contrast, they showed normal levels of social interaction, anxiety-like behavior, and learning and memory. Basal brain rhythms in Pv-Cre;Shank2fl/fl mice, measured by electroencephalography, were normal, but susceptibility to pentylenetetrazole (PTZ)-induced seizures was decreased. These results suggest that Shank2 deletion in PV-positive neurons leads to hyperactivity, enhanced self-grooming and suppressed brain excitation
beta Pix heterozygous mice have defects in neuronal morphology and social interaction
No full textbeta Pix activates Rho family small GTPases, Rac1 and Cdc42 as a guanine nucleotide exchange factor. Although overexpression of beta Pix in cultured neurons indicates that beta Pix is involved in spine morphogenesis and synapse formation in vitro, the in vivo role of beta Pix in the neuron is not well understood. Recently, we generated beta Pix knockout mice that showed lethality at embryonic day 9.5. Here, we investigate the neuronal role of beta Pix using beta Pix heterozygous mice that are viable and fertile. beta Pix heterozygous mice show decreased expression levels of beta Pix proteins in various tissues including the brain. Cultured hippocampal neurons from beta Pix heterozygous mice show a decrease in neurite length and complexity as well as synaptic density. Both excitatory and inhibitory synapse densities are decreased in these neurons. Golgi-staining of hippocampal tissues from the brain of these mice show reduced dendritic complexity and spine density in the hippocampal neurons. Expression levels of NMDA- and AMPA-receptor subunits and Git1 protein in hippocampal tissues are also decreased in these mice. Behaviorally, beta Pix heterozygous mice exhibit impaired social interaction. Altogether, these results indicate that beta Pix is required for neurite morphogenesis and synapse formation, and the reduced expression of beta Pix proteins results in a defect in social behavior. (C) 2019 Elsevier Inc. All rights reserved.
Cell-Type-Specific Shank2 Deletion in Mice Leads to Differential Synaptic and Behavioral Phenotypes
No full textShank2 is an excitatory postsynaptic scaffolding protein implicated in synaptic regulation and psychiatric disorders including autism spectrum disorders. Conventional Shank2-mutant (Shank2−/−) mice display several autistic-like behaviors, including social deficits, repetitive behaviors, hyperactivity, and anxiety-like behaviors. However, cell-type-specific contributions to these behaviors have remained largely unclear. Here, we deleted Shank2 in specific cell types and found that male mice lacking Shank2 in excitatory neurons (CaMKII-Cre;Shank2fl/fl) show social interaction deficits and mild social communication deficits, hyperactivity, and anxiety-like behaviors. In particular, male mice lacking Shank2 in GABAergic inhibitory neurons (Viaat-Cre;Shank2fl/fl) display social communication deficits, repetitive self-grooming, and mild hyperactivity. These behavioral changes were associated with distinct changes in hippocampal and striatal synaptic transmission in the two mouse lines. These results indicate that cell-type-specific deletions of Shank2 in mice lead to differential synaptic and behavioral abnormalities. ©2018 the author
Enhanced neuronal activity in the medial prefrontal cortex during social approach behavior
No full textAlthough the medial prefrontal cortex (mPFC) is known to play a crucial role in rodent social behavior, little is known aboutmPFCneural correlates of social behavior. In the present study,weexamined single-neuron activity in themPFCof mice performing a modified version of the three-chamber test. We found that a subset of mPFC neurons elevate discharge rates when approaching a stranger mouse but not when approaching an inanimate object or an empty chamber. Our results reveal mPFC neural activity that is correlated with social approach behavior in a widely used social-interaction paradigm. These findings might be helpful for future investigations ofmPFCneural processes underlying social interaction in health and disease. © 2016 The Authors7711Nsciescopu
NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors
No full textNetrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3−/− mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3−/− mice, and the Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3−/− mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3−/− mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3β signaling, LTD, and locomotive and cognitive behaviors.</div
Who Was Edmund Lee?
No full textLocal author Peggy Donoho discusses her pioneer ancestor, Edmund Lee, and her work to preserve their family cemetery
The Future of Canadian Climate Policy — with Marc Lee
No full textMarc Lee is a Senior Economist at the Canadian Centre for Policy Alternatives\u27 BC Office. In addition to tracking federal and provincial budgets and economic trends, Marc has published on a range of topics from poverty and inequality to globalization and international trade to public services and regulation. Marc is the Co-Director of the Climate Justice Project, a research partnership with UBC\u27s School of Community and Regional Planning that examines the links between climate change policies and social justice.Resources:Climate Justice Project: www.policyalternatives.ca/projects/cli…tice-projectMarc Lee\u27s Posts on Policy Note: www.policynote.ca/author/marclee/Canadian Centre for Policy Alternatives: www.policyalternatives.ca/Marc\u27s Twitter: twitter.com/MarcLeeCCPA International Panel on Climate Change, 2021 report: www.ipcc.ch/report/ar6/wg1
Dr. Aleksandra Sznajder Lee – Faculty Author Interview
No full textDr. Aleksandra Sznajder Lee, Associate Professor of Political Science, discusses her new book, Transnational Capitalism in East Central Europe’s Heavy Industry, published recently by the University of Michigan Press. Focusing on the steel industry during the post-communist transition from 1989 through 2009, Dr. Sznajder Lee traces the transformation of flagship state enterprises in the Czech Republic, Poland, Romania, and Slovakia into the subsidiaries of large, international corporations
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