scholarly journals Targeting barrel field spiny stellate cells using a vesicular monoaminergic transporter 2-Cre mouse line

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fabio B. Freitag ◽  
Aikeremu Ahemaiti ◽  
Hannah M. Weman ◽  
Katharina Ambroz ◽  
Malin C. Lagerström
Keyword(s):  
Cortical Neurons ◽  
Glutamate Transporter ◽  
Stellate Cells ◽  
Apical Dendrite ◽  
Sequencing Analysis ◽  
Field Development ◽  
Barrel Field ◽  
Adult Mice ◽  
Thalamocortical Projections ◽  
Glutamate Transporter 1

AbstractRodent primary somatosensory cortex (S1) is organized in defined layers, where layer IV serves as the main target for thalamocortical projections. Serotoninergic signaling is important for the organization of thalamocortical projections and consequently proper barrel field development in rodents, and the vesicular monoamine transporter 2 (VMAT2) can be detected locally in layer IV S1 cortical neurons in mice as old as P10, but the identity of the Vmat2-expressing neurons is unknown. We here show that Vmat2 mRNA and also Vmat2-Cre recombinase are still expressed in adult mice in a sub-population of the S1 cortical neurons in the barrel field. The Vmat2-Cre cells showed a homogenous intrinsically bursting firing pattern determined by whole-cell patch-clamp, localized radial densely spinous basal dendritic trees and almost exclusively lack of apical dendrite, indicative of layer IV spiny stellate cells. Single cell mRNA sequencing analysis showed that S1 cortical Vmat2-Cre;tdTomato cells express the layer IV marker Rorb and mainly cluster with layer IV neurons, and RNAscope analysis revealed that adult Vmat2-Cre neurons express Vmat2 and vesicular glutamate transporter 1 (Vglut1) and Vglut2 mRNA to a high extent. In conclusion, our analysis shows that cortical Vmat2 expression is mainly confined to layer IV neurons with morphological, electrophysiological and transcriptional characteristics indicative of spiny stellate cells.

scholarly journals Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Glia ◽  
2020 ◽  
Author(s):  
Eva Perez‐Jimenez ◽  
Rosa Viana ◽  
Carmen Muñoz‐Ballester ◽  
Carlos Vendrell‐Tornero ◽  
Raquel Moll‐Diaz ◽  
...  
Keyword(s):  
Glutamate Transporter ◽  
Lafora Disease ◽  
Glutamate Transporter 1

scholarly journals Activation of Glutamate Transporter-1 (GLT-1) Confers Sex-Dependent Neuroprotection in Brain Ischemia

2021 ◽  
Vol 11 (1) ◽  
pp. 76
Author(s):  
Flavia A. Tejeda-Bayron ◽  
David E. Rivera-Aponte ◽  
Christian J. Malpica-Nieves ◽  
Gerónimo Maldonado-Martínez ◽  
Héctor M. Maldonado ◽  
...  
Keyword(s):  
Infarct Size ◽  
Glutamate Transporter ◽  
Triphenyltetrazolium Chloride ◽  
Stroke Outcomes ◽  
Female Mice ◽  
Protein Levels ◽  
Translational Activator ◽  
Glutamate Transporter 1 ◽  
Sensorimotor Performance

Stroke is one of the leading causes of long-term disability. During ischemic stroke, glutamate is released, reuptake processes are impaired, and glutamate promotes excitotoxic neuronal death. Astrocytic glutamate transporter 1 (GLT-1) is the major transporter responsible for removing excess glutamate from the extracellular space. A translational activator of GLT-1, LDN/OSU 0212320 (LDN) has been previously developed with beneficial outcomes in epileptic animal models but has never been tested as a potential therapeutic for ischemic strokes. The present study evaluated the effects of LDN on stroke-associated brain injury. Male and female mice received LDN or vehicle 24 h before or 2 h after focal ischemia was induced in the sensorimotor cortex. Sensorimotor performance was determined using the Rung Ladder Walk and infarct area was assessed using triphenyltetrazolium chloride staining. Males treated with LDN exhibited upregulated GLT-1 protein levels, significantly smaller infarct size, and displayed better sensorimotor performance in comparison to those treated with vehicle only. In contrast, there was no upregulation of GLT-1 protein levels and no difference in infarct size or sensorimotor performance between vehicle- and LDN-treated females. Taken together, our results indicate that the GLT-1 translational activator LDN improved stroke outcomes in young adult male, but not female mice.

scholarly journals Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter

2007 ◽  
Vol 27 (9) ◽  
pp. 1540-1552 ◽  
Author(s):  
Selva Baltan Tekkök ◽  
ZuCheng Ye ◽  
Bruce R Ransom
Keyword(s):  
White Matter ◽  
High Performance ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Kainate Receptors ◽  
Adult Mice ◽  
Direct Exposure ◽  
Glutamate Receptor Agonist

Axonal injury and dysfunction in white matter (WM) are caused by many neurologic diseases including ischemia. We characterized ischemic injury and the role of glutamate-mediated excitotoxicity in a purely myelinated WM tract, the mouse optic nerve (MON). For the first time, excitotoxic WM injury was directly correlated with glutamate release. Oxygen and glucose deprivation (OGD) caused duration-dependent loss of axon function in optic nerves from young adult mice. Protection of axon function required blockade of both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or removal of extracellular Ca2+. Blockade of N-methyl-D-aspartate receptors did not preserve axon function. Curiously, even extended periods of direct exposure to glutamate or kainate or AMPA failed to induce axon dysfunction. Brief periods of OGD, however, caused glutamate receptor agonist exposure to become toxic, suggesting that ionic disruption enabled excitotoxic injury. Glutamate release, directly measured using quantitative high-performance liquid chromatography, occurred late during a 60-mins period of OGD and was due to reversal of the glutamate transporter. Brief periods of OGD (i.e., 15 mins) did not cause glutamate release and produced minimal injury. These results suggested that toxic glutamate accumulation during OGD followed the initial ionic changes mediating early loss of excitability. The onset of glutamate release was an important threshold event for irreversible ischemic injury. Regional differences appear to exist in the specific glutamate receptors that mediate WM ischemic injury. Therapy for ischemic WM injury must be designed accordingly.

scholarly journals Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism

2020 ◽  
Author(s):  
Owen Y Chao ◽  
Salil S Pathak ◽  
Hao Zhang ◽  
Nathan Dunaway ◽  
Jay-Shake Li ◽  
...  
Keyword(s):  
Fragile X ◽  
Glutamate Transporter ◽  
Dorsal Striatum ◽  
Autism Spectrum ◽  
Acid Decarboxylase ◽  
Therapeutic Effects ◽  
Spatial Coupling ◽  
Motivated Behavior ◽  
Object Based ◽  
Glutamate Transporter 1

Abstract The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher “complexity” and lower “texture”. Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.

scholarly journals TET3 regulates DNA hydroxymethylation of neuroprotective genes following focal ischemia

2020 ◽  
pp. 0271678X2091296
Author(s):  
Kahlilia C Morris-Blanco ◽  
Anil K Chokkalla ◽  
Mario J Bertogliat ◽  
Raghu Vemuganti
Keyword(s):  
Epigenetic Modification ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Dna Hydroxymethylation ◽  
Adult Mice ◽  
Genome Wide ◽  
Endogenous Protection ◽  
Genomic Regions

The 5-hydroxymethylcytosine (5hmC) epigenetic modification is highly enriched in the CNS and a critical modulator of neuronal function and development. We found that cortical 5hmC was enhanced from 5 min to three days of reperfusion following focal ischemia in adult mice. Blockade of the 5hmC-producing enzyme ten-eleven translocase 3 (TET3) increased edema, infarct volume, and motor function impairments. To determine the mechanism by which TET3 provides ischemic neuroprotection, we assessed the genomic regions where TET3 modulates 5hmC. Genome-wide sequencing analysis of differentially hydroxymethylated regions (DhMRs) revealed that focal ischemia robustly increased 5hmC at the promoters of thousands of genes in a TET3-dependent manner. TET3 inhibition reduced 5hmC at the promoters of neuroprotective genes involved in cell survival, angiogenesis, neurogenesis, antioxidant defense, DNA repair, and metabolism demonstrating a role for TET3 in endogenous protection against stroke. The mRNA expression of several genes with known involvement in ischemic neuroprotection were also reduced with TET3 knockdown in both male and female mice, establishing a correlation between decreased promoter 5hmC levels and decreased gene expression. Collectively, our results indicate that TET3 globally increases 5hmC at regulatory regions and overwhelmingly modulates 5hmC in several neuroprotective pathways that may improve outcome after ischemic injury.

scholarly journals Effects of Repeated 20-Hz Electrical Stimulation on Functional Recovery Following Peripheral Nerve Injury

2019 ◽  
Vol 33 (9) ◽  
pp. 775-784 ◽  
Author(s):  
Sohee Park ◽  
Cai-yue Liu ◽  
Patricia J. Ward ◽  
Poonam B. Jaiswal ◽  
Arthur W. English
Keyword(s):  
Electrical Stimulation ◽  
Peripheral Nerves ◽  
Treadmill Exercise ◽  
Glutamate Transporter ◽  
Vesicular Glutamate Transporter ◽  
Single Application ◽  
Repeated Applications ◽  
Peripheral Axon ◽  
Glutamate Transporter 1 ◽  
Muscle Responses

One hour of 20-Hz continuous electrical stimulation (ES) applied at the time of injury promotes the regeneration of axons in cut peripheral nerves. A more robust enhancement of peripheral axon regeneration is achieved by 2 weeks of daily treadmill exercise. We investigated whether repeated applications of brief ES (mES) would be more effective in promoting regeneration than a single application. Sciatic nerves of C57B6 mice were cut and repaired by end-to-end anastomosis. At that time and every third day for 2 weeks, the repaired nerve was stimulated for 1 hour at 20 Hz. In controls, injured mice were either untreated or treated with ES only once. Direct muscle responses recorded from reinnervated muscles in awake animals were observed earlier both in mice treated with ES and mES than untreated controls. Their amplitudes increased progressively over the post transection study period, but the rate of this progression was increased significantly only in animals treated once with ES. Monosynaptic H reflexes recovered to pretransection levels in both untreated and singly treated mice but in the animals treated repeatedly, they were maintained at more than twice that of the same reflexes recorded prior to injury. In anatomical analyses, both excitatory and inhibitory synaptic contacts with the cell bodies of injured motoneurons, including those expressing the vesicular glutamate transporter 1 (VGLUT1), were sustained in mice treated repeatedly but not in singly treated or untreated mice. Repeated ES does not enhance the rate of restoration of functional muscle reinnervation and results in the retention of exaggerated reflexes.

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