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Glutamatergic dysregulation

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https://www.readbyqxmd.com/read/29703731/dysregulation-of-sphingolipid-metabolism-contributes-to-bortezomib-induced-neuropathic-pain
#1
Katherine Stockstill, Timothy M Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W Little, Kathryn Braden, Filomena Lauro, Luigino Antonio Giancotti, Caron Mitsue Harada, Ruchi Yadav, Wen Hua Xiao, Jack M Lionberger, William L Neumann, Gary J Bennett, Han-Rong Weng, Sarah Spiegel, Daniela Salvemini
The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain...
April 27, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29604382/the-role-of-depressive-subtypes-within-the-neuroinflammation-hypothesis-of-major-depressive-disorder
#2
Marie Woelfer, Vanessa Kasties, Sascha Kahlfuss, Martin Walter
Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points towards an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset...
March 28, 2018: Neuroscience
https://www.readbyqxmd.com/read/29578033/propranolol-produces-short-term-facilitation-of-extinction-in-a-rabbit-model-of-post-traumatic-stress-disorder
#3
Lauren B Burhans, Carrie A Smith-Bell, Bernard G Schreurs
Post-traumatic stress disorder (PTSD) is a learning-based anxiety disorder with significant public health challenges due to difficulties in treating the complex, multiple symptomology. We have developed an animal model of PTSD, based on Pavlovian eyeblink conditioning in rabbits, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). We have found previously that unpaired extinction is ideal for reducing both CRs and CRM simultaneously and shows sensitivity to systemic serotonergic and glutamatergic manipulations...
March 22, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29577983/age-related-nmda-signaling-alterations-in-sod2-deficient-mice
#4
Francisco J Carvajal, Rodrigo G Mira, Maximiliano Rovegno, Alicia N Minniti, Waldo Cerpa
Oxidative stress affects the survival and function of neurons. Hence, they have a complex and highly regulated machinery to handle oxidative changes. The dysregulation of this antioxidant machinery is associated with a wide range of neurodegenerative conditions. Therefore, we evaluated signaling alterations, synaptic properties and behavioral performance in 2 and 6-month-old heterozygous manganese superoxide dismutase knockout mice (SOD2+/- mice). We found that their low antioxidant capacity generated direct oxidative damage in proteins, lipids, and DNA...
March 22, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29568566/could-dietary-glutamate-be-contributing-to-the-symptoms-of-obsessive-compulsive-disorder
#5
Kathleen F Holton, Elizabeth W Cotter
A 50-year-old man who had suffered from daily obsessive-compulsive disorder (OCD) symptoms for 39 years, in addition to fibromyalgia and irritable bowel syndrome symptoms, was enrolled in a randomized double-blind placebo-controlled clinical trial to test the effects of a low-glutamate diet on fibromyalgia/irritable bowel syndrome symptoms. After 1 month on the low-glutamate diet all of his symptoms remitted, including his OCD, which had previously been nonresponsive to pharmacological treatment. This case study is limited by self-report of symptoms; however, glutamatergic neurotransmission appears to be dysregulated in OCD, suggesting biological plausibility for this observation...
March 2018: Future Science OA
https://www.readbyqxmd.com/read/29550939/circuit-selective-properties-of-glutamatergic-inputs-to-the-rat-prelimbic-cortex-and-their-alterations-in-neuropathic-pain
#6
Crystle J Kelly, Marco Martina
Functional deactivation of the prefrontal cortex (PFC) is a critical step in the neuropathic pain phenotype. We performed optogenetic circuit dissection to study the properties of ventral hippocampal (vHipp) and thalamic (MDTh) inputs to L5 pyramidal cells in acute mPFC slices and to test whether alterations in these inputs contribute to mPFC deactivation in neuropathic pain. We found that: (1) both the vHipp and MDTh inputs elicit monosynaptic excitatory and polysynaptic inhibitory currents. (2) The strength of the excitatory MDTh input is uniform, while the vHipp input becomes progressively stronger along the dorsal-ventral axis...
March 17, 2018: Brain Structure & Function
https://www.readbyqxmd.com/read/29540546/regulation-of-nociceptive-glutamatergic-signaling-by-presynaptic-kv3-4-channels-in-the-rat-spinal-dorsal-horn
#7
Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C Lepore, Manuel Covarrubias
Presynaptic voltage-gated K+ (Kv) channels in dorsal root ganglion (DRG) neurons are thought to regulate nociceptive synaptic transmission in the spinal dorsal horn. However, the Kv channel subtypes responsible for this critical role have not been identified. The Kv3.4 channel is particularly important because it is robustly expressed in DRG nociceptors, where it regulates action potential (AP) duration. Furthermore, Kv3.4 dysfunction is implicated in the pathophysiology of neuropathic pain in multiple pain models...
April 11, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29535626/trace-amine-associated-receptor-1-taar1-modulation-of-food-reward
#8
REVIEW
Catherine F Moore, Valentina Sabino, Pietro Cottone
Eating disorders and some forms of obesity are characterized by addictive-like, compulsive eating behavior which contains numerous similarities with compulsive drug use. Food intake is in part mediated by reward and reinforcement processes that can become dysregulated in these disorders. Additionally, impairments in inhibitory control regulation of reward-related responding can cause or further exacerbate binge and compulsive eating. Dysfunctions in two neurotransmitter systems in the mesocorticolimbic pathway, dopamine and glutamate, are thought to contribute to maladaptive eating behaviors...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29514086/transcriptional-dysregulation-in-postnatal-glutamatergic-progenitors-contributes-to-closure-of-the-cortical-neurogenic-period
#9
Vanessa Donega, Guillaume Marcy, Quentin Lo Giudice, Stefan Zweifel, Diane Angonin, Roberto Fiorelli, Djoher Nora Abrous, Sylvie Rival-Gervier, Muriel Koehl, Denis Jabaudon, Olivier Raineteau
Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency...
March 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29496544/frontotemporal-dysregulation-of-the-snare-protein-interactome-is-associated-with-faster-cognitive-decline-in-old-age
#10
Alfredo Ramos-Miguel, Andrea A Jones, Ken Sawada, Alasdair M Barr, Thomas A Bayer, Peter Falkai, Sue E Leurgans, Julie A Schneider, David A Bennett, William G Honer
The molecular underpinnings associated with cognitive reserve remain poorly understood. Because animal models fail to fully recapitulate the complexity of human brain aging, postmortem studies from well-designed cohorts are crucial to unmask mechanisms conferring cognitive resistance against cumulative neuropathologies. We tested the hypothesis that functionality of the SNARE protein interactome might be an important resilience factor preserving cognitive abilities in old age. Cognition was assessed annually in participants from the Rush "Memory and Aging Project" (MAP), a community-dwelling cohort representative of the overall aging population...
June 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29491011/celecoxib-ameliorates-seizure-susceptibility-in-autosomal-dominant-lateral-temporal-epilepsy
#11
Lin Zhou, Liang Zhou, Li-da Su, Sheng-Long Cao, Ya-Jun Xie, Na Wang, Chong-Yu Shao, Ya-Nan Wang, Jia-Huan Zhou, John K Cowell, Ying Shen
Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that glutamatergic transmission is altered in LGI1 mutant mice, and seizures can be reduced by restoring LGI1 function. Yet, the mechanism underlying ADLTE is unclear. Here, we propose that seizures in male LGI1 -/- mice are due to nonsynaptic epileptiform activity in cortical neurons. We examined the intrinsic excitability of pyramidal neurons in the temporal cortex of male LGI1 -/- mice and found that the voltage-gated K+ channel Kv1...
March 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29491010/maternal-and-early-postnatal-immune-activation-produce-dissociable-effects-on-neurotransmission-in-mpfc-amygdala-circuits
#12
Yan Li, Galen Missig, Beate C Finger, Samantha M Landino, Abigail J Alexander, Emery L Mokler, James O Robbins, Yunona Manasian, Woori Kim, Kwang-Soo Kim, Christopher J McDougle, William A Carlezon, Vadim Y Bolshakov
Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including autism spectrum disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors, and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12...
March 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29486374/the-therapeutic-potential-of-metabotropic-glutamate-receptor-modulation-for-schizophrenia
#13
REVIEW
Branden J Stansley, P Jeffrey Conn
Accumulating evidence suggests that a dysregulation of the glutamatergic system exists in the brains of schizophrenia patients. The metabotropic glutamate (mGlu) receptors are being investigated as novel drug targets for this disease, and have shown promise in both preclinical and clinical studies. Activation of mGlu5 receptors may be efficacious for several symptom domains (positive, negative, and cognitive) and the potential for targeting mGlu5 receptors has been bolstered by recent research on mitigating toxicity profiles associated with mGlu5 activation...
February 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29467003/extracellular-%C3%AE-synuclein-levels-are-regulated-by-neuronal-activity
#14
Kaoru Yamada, Takeshi Iwatsubo
BACKGROUND: α-Synuclein is a presynaptic protein abundant in the cytoplasmic compartment of neurons, whereas its presence in the extracellular space has also been observed under physiological conditions. Extracellular α-synuclein has pathological significance, exhibiting cellular toxicity and impairment of synaptic transmission. Notably, misfolded α-synuclein drives the cell-to-cell propagation of pathology via the extracellular space. However, the primary mechanism that regulates the extracellular levels of α-synuclein remains to be determined...
February 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29459374/rescue-of-learning-and-memory-deficits-in-the-human-nonsyndromic-intellectual-disability-cereblon-knock-out-mouse-model-by-targeting-the-amp-activated-protein-kinase-mtorc1-translational-pathway
#15
Charlotte C Bavley, Richard C Rice, Delaney K Fischer, Amanda K Fakira, Maureen Byrne, Maria Kosovsky, Bryant K Rizzo, Dolores Del Prete, Armin Alaedini, Jose A Morón, Joseph J Higgins, Luciano D'Adamio, Anjali M Rajadhyaksha
A homozygous nonsense mutation in the cereblon ( CRBN ) gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male Crbn knock-out ( Crbn KO ) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29444988/nmda-type-glutamate-receptor-activation-promotes-vascular-remodeling-and-pulmonary-arterial-hypertension
#16
Sébastien J Dumas, Gilles Bru-Mercier, Audrey Courboulin, Marceau Quatredeniers, Catherine Rücker-Martin, Fabrice Antigny, Morad K Nakhleh, Benoit Ranchoux, Elodie Gouadon, Maria-Candida Vinhas, Matthieu Vocelle, Nicolas Raymond, Peter Dorfmüller, Elie Fadel, Frédéric Perros, Marc Humbert, Sylvia Cohen-Kaminsky
Background -Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N-methyl-D-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells, but its role in PAH is unknown...
February 14, 2018: Circulation
https://www.readbyqxmd.com/read/29425773/cocaine-and-amphetamine-regulated-transcript-peptide-cart-alleviates-mk-801-induced-schizophrenic-dementia-like-symptoms
#17
Chandrashekhar D Borkar, Ashish P Bharne, B Nagalakshmi, Amul J Sakharkar, Nishikant K Subhedar, Dadasaheb M Kokare
Exaggerated thoughts, diminished mood and impaired cognition are the hallmarks of the schizophrenia-like condition. These symptoms are attributed to the dysregulation of dopamine and glutamate signaling in the brain. Since cocaine- and amphetamine-regulated transcript peptide (CART) modulates actions of dopamine as well as glutamate, we tested the role of this peptide in MK-801-induced schizophrenic dementia-like condition. MK-801-treated rats were allowed to interact with conspecific juvenile and tested for short-term (30-min) and long-term (24-h) social memory acquisition and recall...
April 1, 2018: Neuroscience
https://www.readbyqxmd.com/read/29377412/high-fat-diet-induces-a-neurometabolic-state-characterized-by-changes-in-glutamate-and-n-acetylaspartate-pools-associated-with-early-glucose-intolerance-an-in-vivo-multimodal-mri-study
#18
Mário Ribeiro, João Castelhano, Lorena I Petrella, José Sereno, Tiago Rodrigues, Christian Neves, Liliana Letra, Filipa I Baptista, Raquel Seiça, Paulo Matafome, Miguel Castelo-Branco
BACKGROUND: Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial...
January 26, 2018: Journal of Magnetic Resonance Imaging: JMRI
https://www.readbyqxmd.com/read/29368945/acute-high-fat-diet-upregulates-glutamatergic-signaling-in-the-dorsal-motor-nucleus-of-the-vagus
#19
Courtney Clyburn, R Alberto Travagli, Kirsteen N Browning
Obesity is associated with dysregulation of vagal neurocircuits controlling gastric functions, including food intake and energy balance. In the short term, however, caloric intake is regulated homeostatically, although the precise mechanisms responsible are unknown. The present study examined the effects of acute high fat diet (HFD) on glutamatergic neurotransmission within central vagal neurocircuits and its effects on gastric motility. Sprague-Dawley rats were fed a control or HFD diet (14% or 60% kcal from fat, respectively) for 3-5 days...
January 25, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29315577/bidirectional-variation-in-glutamate-efflux-in-the-medial-prefrontal-cortex-induced-by-selective-positive-and-negative-allosteric-mglur5-modulators
#20
Sarah N Isherwood, Trevor W Robbins, Jeffrey W Dalley, Anton Pekcec
Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention-deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) remains unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non-competitive NMDA receptor antagonist dizocilpine (or MK801) in rats...
January 6, 2018: Journal of Neurochemistry
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