scholarly journals Disruption of GABA or glutamate release from POMC neurons in the adult mouse does not affect metabolic end points

2020 ◽  
Vol 319 (5) ◽  
pp. R592-R601
Author(s):  
Andrew R. Rau ◽  
Connie M. King ◽  
Shane T. Hentges
Keyword(s):  
Amino Acid ◽  
Transmitter Release ◽  
Adult Mouse ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Vesicular Glutamate Transporter ◽  
Metabolic Phenotypes ◽  
Adult Mice ◽  
Physiological Processes

Proopiomelanocortin (POMC) neurons contribute to the regulation of many physiological processes; the majority of which have been attributed to the release of peptides produced from the POMC prohormone such as α-MSH, which plays key roles in food intake and metabolism. However, it is now clear that POMC neurons also release amino acid transmitters that likely contribute to the overall function of POMC cells. Recent work indicates that constitutive deletion of these transmitters can affect metabolic phenotypes, but also that the expression of GABAergic or glutamatergic markers changes throughout development. The goal of the present study was to determine whether the release of glutamate or GABA from POMC neurons in the adult mouse contributes notably to energy balance regulation. Disturbed release of glutamate or GABA specifically from POMC neurons in adult mice was achieved using a tamoxifen-inducible Cre construct ( Pomc-CreERT2) expressed in mice also carrying floxed versions of Slc17a6 (vGlut2) or Gad1 and Gad2, encoding the vesicular glutamate transporter type 2 and GAD67 and GAD65 proteins, respectively. All mice in the experiments received tamoxifen injections, but control mice lacked the tamoxifen-inducible Cre sequence. Body weight was unchanged in Gad1- and Gad2- or vGlut2-deleted female and male mice. Additionally, no significant differences in glucose tolerance or refeeding after an overnight fast were observed. These data collectively suggest that the release of GABA or glutamate from POMC neurons in adult mice does not significantly contribute to the metabolic parameters tested here. In light of prior work, the data also suggest that amino acid transmitter release from POMC cells may contribute to separate functions in the adult versus the developing mouse.

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 Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kenneth A Pelkey ◽  
Daniela Calvigioni ◽  
Calvin Fang ◽  
Geoffrey Vargish ◽  
Tyler Ekins ◽  
...  
Keyword(s):  
Vitamin B6 ◽  
Direct Evidence ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Gabaergic Interneurons ◽  
Adult Mice ◽  
Cortical Interneurons ◽  
Glutamatergic Signaling ◽  
Paired Recording ◽  
Vitamin B6 Deficiency

In violation of Dale’s principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.

scholarly journals Hypophysiotropic Thyrotropin-Releasing Hormone and Corticotropin-Releasing Hormone Neurons of the Rat Contain Vesicular Glutamate Transporter-2

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 341-347 ◽  
Author(s):  
Erik Hrabovszky ◽  
Gábor Wittmann ◽  
Gergely F. Turi ◽  
Zsolt Liposits ◽  
Csaba Fekete
Keyword(s):  
Glutamate Release ◽  
Glutamate Transporter ◽  
Microscopic Analysis ◽  
Male Rat ◽  
Confocal Laser ◽  
Vesicular Glutamate Transporter ◽  
Releasing Hormone ◽  
Large Numbers ◽  
Adult Male Rat ◽  
Dual Label

TRH and CRH are secreted into the hypophysial portal circulation by hypophysiotropic neurons located in parvicellular subdivisions of the hypothalamic paraventricular nucleus (PVH). Recently these anatomical compartments of the PVH have been shown to contain large numbers of glutamatergic neurons expressing type 2 vesicular glutamate transporter (VGLUT2). In this report we presented dual-label in situ hybridization evidence that the majority (>90%) of TRH and CRH neurons in the PVH of the adult male rat express the mRNA encoding VGLUT2. Dual-label immunofluorescent studies followed by confocal laser microscopic analysis of the median eminence also demonstrated the occurrence of VGLUT2 immunoreactivity within TRH and CRH axon varicosities, suggesting terminal glutamate release from these neuroendocrine systems. These data together indicate that the hypophysiotropic TRH and CRH neurons possess glutamatergic characteristics. Future studies will need to address the physiological significance of the endogenous glutamate content in these neurosecretory systems in the neuroendocrine regulation of thyroid and adrenal functions.

scholarly journals Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice

2018 ◽  
Vol 115 (49) ◽  
pp. E11532-E11541 ◽  
Author(s):  
Hui Shen ◽  
Rosa Anna M. Marino ◽  
Ross A. McDevitt ◽  
Guo-Hua Bi ◽  
Kai Chen ◽  
...  
Keyword(s):  
Glutamate Release ◽  
Glutamate Transporter ◽  
Dopamine Neurons ◽  
Therapeutic Interventions ◽  
Vesicular Glutamate Transporter ◽  
Increased Risk ◽  
Locomotor Impairment ◽  
Functional Consequences ◽  
Midbrain Dopamine ◽  
And Function

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson’s disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

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