Sujata Saraswat Ohri, Michael D Forston, Scott A Myers, Brandon L Brown, Kariena R Andres, Russell M Howard, Yonglin Gao, Yu Liu, Douglas R Cavener, Michal Hetman, Scott R Whittemore
After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central to that response is PERK signaling, which ultimately initiates a pro-apoptotic response if cellular homeostasis cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive functional consequences and determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) and chronic (6 weeks post-SCI) effects of conditionally deleting Perk from OLs prior to SCI...
April 8, 2024: Glia
Erik Späte, Baoyu Zhou, Ting Sun, Kathrin Kusch, Ebrahim Asadollahi, Sophie B Siems, Constanze Depp, Hauke B Werner, Gesine Saher, Johannes Hirrlinger, Wiebke Möbius, Klaus-Armin Nave, Sandra Goebbels
Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support...
April 8, 2024: Glia
Romina Barreto-Núñez, Louis-Charles Béland, Hejer Boutej, Vincent Picher-Martel, Nicolas Dupré, Luis Barbeito, Jasna Kriz
Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo...
April 5, 2024: Glia
Negar Asadian, Andrea Aprico, Moore Chen, Daniel Yuen, Angus P R Johnston, Trevor J Kilpatrick, Michele D Binder
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, axonal damage and, for the majority of people, a decline in neurological function in the long-term. Remyelination could assist in the protection of axons and their functional recovery, but such therapies are not, as yet, available. The TAM (Tyro3, Axl, and MERTK) receptor ligand GAS6 potentiates myelination in vitro and promotes recovery in pre-clinical models of MS. However, it has remained unclear which TAM receptor is responsible for transducing this effect and whether post-translational modification of GAS6 is required...
April 4, 2024: Glia
Antonia L Schmidt, Marco Kremp, Takaaki Aratake, Siying Cui, Yifeng Lin, Xiaowen Zhong, Q Richard Lu, Chengfu Zhang, Mengsheng Qiu, Tim Aberle, Michael Wegner
Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors...
March 28, 2024: Glia
Olivia B Taylor, Snehal P Patel, Evan C Hawthorn, Heithem M El-Hodiri, Andy J Fischer
The purpose of this study was to investigate how ID factors regulate the ability of Müller glia (MG) to reprogram into proliferating MG-derived progenitor cells (MGPCs) in the chick retina. We found that ID1 is transiently expressed by maturing MG (mMG), whereas ID4 is maintained in mMG in embryonic retinas. In mature retinas, ID4 was prominently expressed by resting MG, but following retinal damage ID4 was rapidly upregulated and then downregulated in MGPCs. By contrast, ID1, ID2, and ID3 were low in resting MG and then upregulated in MGPCs...
March 21, 2024: Glia
Isabella Crisci, Sara Bonzano, Zinter Nicolas, Eleonora Dallorto, Paolo Peretto, Wojciech Krezel, Silvia De Marchis
Tamoxifen-inducible systems are widely used in research to control Cre-mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off-target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)-induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four-day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons...
March 21, 2024: Glia
Lara Rogerson-Wood, Claire S Goldsbury, Atomu Sawatari, Catherine A Leamey
Brain function is critically dependent on correct circuit assembly. Microglia are well-known for their important roles in immunological defense and neural plasticity, but whether they can also mediate experience-induced correction of miswired circuitry is unclear. Ten-m3 knockout (KO) mice display a pronounced and stereotyped visuotopic mismapping of ipsilateral retinal inputs in their visual thalamus, providing a useful model to probe circuit correction mechanisms. Environmental enrichment (EE) commenced around birth, but not later in life, can drive a partial correction of the most mismapped retinal inputs in Ten-m3 KO mice...
March 21, 2024: Glia
Ana Cristina Ojalvo-Sanz, Carolina Pernia-Solanilla, Laura López-Mascaraque
Astrocytes represent a diverse and morphologically complex group of glial cells critical for shaping and maintaining nervous system homeostasis, as well as responding to injuries. Understanding the origins of astroglial heterogeneity, originated from a limited number of progenitors, has been the focus of many studies. Most of these investigations have centered on protoplasmic and pial astrocytes, while the clonal relationship of fibrous astrocytes or juxtavascular astrocytes has remained relatively unexplored...
March 20, 2024: Glia
Océane Mercier, Pascale P Quilichini, Karine Magalon, Florian Gil, Antoine Ghestem, Fabrice Richard, Thomas Boudier, Myriam Cayre, Pascale Durbec
In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination...
May 2024: Glia
Valerio E C Piscopo, Alexandra Chapleau, Gabriela J Blaszczyk, Julien Sirois, Zhipeng You, Vincent Soubannier, Carol X-Q Chen, Geneviève Bernard, Jack P Antel, Thomas M Durcan
Oligodendrocytes (OLs) are key players in the central nervous system, critical for the formation and maintenance of the myelin sheaths insulating axons, ensuring efficient neuronal communication. In the last decade, the use of human induced pluripotent stem cells (iPSCs) has become essential for recapitulating and understanding the differentiation and role of OLs in vitro. Current methods include overexpression of transcription factors for rapid OL generation, neglecting the complexity of OL lineage development...
March 18, 2024: Glia
Sarah I Palko, Marc R Benoit, Annie Y Yao, Royce Mohan, Riqiang Yan
Alzheimer's Disease (AD) pathogenesis is thought to begin up to 20 years before cognitive symptoms appear, suggesting the need for more sensitive diagnostic biomarkers of AD. In this report, we demonstrated pathological changes in retinal Müller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock-in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30). Despite RTN3 being a canonically neuronal protein, this increase was noted in the retinal Müller glia, confirmed by immunohistochemical characterization...
March 18, 2024: Glia
Joana Gonçalves-Ribeiro, Oksana K Savchak, Sara Costa-Pinto, Joana I Gomes, Rafael Rivas-Santisteban, Alejandro Lillo, Javier Sánchez Romero, Ana M Sebastião, Marta Navarrete, Gemma Navarro, Rafael Franco, Sandra H Vaz
The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+ ) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1 R, A2A R), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2A R or CB1R-A1 R heteromers that ultimately impact mPFC synaptic plasticity...
March 14, 2024: Glia
Aysha M Bhojwani-Cabrera, Alicia Bautista-García, Veronika E Neubrand, Francisco A Membrive-Jiménez, Mattia Bramini, David Martin-Oliva, Miguel A Cuadros, José Luis Marín-Teva, Julio Navascués, Peter Vangheluwe, M Rosario Sepúlveda
Microglia play an important protective role in the healthy nervous tissue, being able to react to a variety of stimuli that induce different intracellular cascades for specific tasks. Ca2+ signaling can modulate these pathways, and we recently reported that microglial functions depend on the endoplasmic reticulum as a Ca2+ store, which involves the Ca2+ transporter SERCA2b. Here, we investigated whether microglial functions may also rely on the Golgi, another intracellular Ca2+ store that depends on the secretory pathway Ca2+ /Mn2+ -transport ATPase isoform 1 (SPCA1)...
March 14, 2024: Glia
André Dietz, Katja Senf, Eva M Neuhaus
Barrier-forming olfactory glia cells, termed sustentacular cells, play important roles for immune defense of the olfactory mucosa, for example as entry sites for SARS-CoV-2 and subsequent development of inflammation-induced smell loss. Here we demonstrate that sustentacular cells express ACKR3, a chemokine receptor that functions both as a scavenger of the chemokine CXCL12 and as an activator of alternative signaling pathways. Differential gene expression analysis of bulk RNA sequencing data obtained from WT and ACKR3 conditional knockout mice revealed upregulation of genes involved in immune defense...
March 13, 2024: Glia
Eman Qarot, Yun Guan, Menachem Hanani
Neurons in sensory ganglia are wrapped completely by satellite glial cells (SGCs). One putative function of SGCs is to regulate the neuronal microenvironment, but this role has received only little attention. In this study we investigated whether the SGC envelope serves a barrier function and how SGCs may control the neuronal microenvironment. We studied this question on short-term (<24 h) cell cultures of dorsal root ganglia and trigeminal ganglia from adult mice, which contain neurons surrounded with SGCs, and neurons that are not...
March 7, 2024: Glia
Ela Bar, Inbar Fischer, May Rokach, Galit Elad-Sfadia, Sophie Shirenova, Omer Ophir, Sari Schokoroy Trangle, Eitan Okun, Boaz Barak
Williams syndrome (WS) is a genetic neurodevelopmental disorder caused by a heterozygous microdeletion, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. We have recently shown that Gtf2i deletion from forebrain excitatory neurons, referred to as Gtf2i conditional knockout (cKO) mice leads to multi-faceted myelination deficits associated with the social behaviors affected in WS. These deficits were potentially mediated also by microglia, as they present a close relationship with oligodendrocytes...
March 7, 2024: Glia
Chaoran Wu, Yu Li, Xinran He, Hao Sun, Shiwen Zhang, Fengsheng Hou, Mengqiu Hu, Aili Lan, Hao Zhang, Long Qi, Huibin Zhang, Hong Liao
Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke...
March 4, 2024: Glia
Jing Zhu, Soojin Park, Se Hoon Kim, Chul Hoon Kim, Kyoung Hoon Jeong, Won-Joo Kim
Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti-inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine-induced status epilepticus (SE)...
February 26, 2024: Glia
Limin Ma, Qingyuan Wu, Yu You, Peng Zhang, Dandan Tan, Minxue Liang, Yunyi Huang, Yuan Gao, Yuenan Ban, Yangmei Chen, Jinxian Yuan
Information exchange between neurons and astrocytes mediated by extracellular vesicles (EVs) is known to play a key role in the pathogenesis of central nervous system diseases. A key driver of epilepsy is the dysregulation of intersynaptic excitatory neurotransmitters mediated by astrocytes. Thus, we investigated the potential association between neuronal EV microRNAs (miRNAs) and astrocyte glutamate uptake ability in epilepsy. Here, we showed that astrocytes were able to engulf epileptogenic neuronal EVs, inducing a significant increase in the glutamate concentration in the extracellular fluid of astrocytes, which was linked to a decrease in glutamate transporter-1 (GLT-1) protein expression...
February 22, 2024: Glia
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