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Glutamatergic dysregulation

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...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
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
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...
February 26, 2018: Neurobiology of Disease
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 non-synaptic 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...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yan Li, Galen Missig, Beate C Finger, Samantha M Landino, Abigail J Alexander, Emery Mokler, James 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...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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 24, 2018: Current Opinion in Pharmacology
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
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, non-syndromic intellectual disability (ARNSID) 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 knockout ( Crbn KO ) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knockout of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior...
February 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
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-hr) social memory acquisition and recall...
February 6, 2018: Neuroscience
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
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
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) is 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
Dong Sun, Xiang-Dong Sun, Lu Zhao, Dae-Hoon Lee, Jin-Xia Hu, Fu-Lei Tang, Jin-Xiu Pan, Lin Mei, Xiao-Juan Zhu, Wen-Cheng Xiong
Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation...
January 8, 2018: Cell Death & Disease
Hong Lin, Jordi Magrane, Elisia M Clark, Sarah M Halawani, Nathan Warren, Amy Rattelle, David R Lynch
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model...
December 19, 2017: Disease Models & Mechanisms
V Reffatto, J D Rasinger, T S Carroll, T Ganay, A-K Lundebye, I Sekler, M Hershfinkel, C Hogstrand
Hexabromocyclododecane (HBCD) is a brominated flame retardant (BFR) that accumulates in humans and affects the nervous system. To elucidate the mechanisms of HBCD neurotoxicity, we used transcriptomic profiling in brains of female mice exposed through their diet to HBCD (199 mg/kg body weight per day) for 28 days and compared with those of neuronal N2A and NSC-19 cell lines exposed to 1 or 2 µM HBCD. Similar pathways and functions were affected both in vivo and in vitro, including Ca2+ and Zn2+ signalling, glutamatergic neuron activity, apoptosis, and oxidative stress...
November 25, 2017: Archives of Toxicology
Andrea Ruiz-Calvo, Irene B Maroto, Raquel Bajo-Grañeras, Anna Chiarlone, Ángel Gaudioso, José J Ferrero, Eva Resel, José Sánchez-Prieto, José A Rodríguez-Navarro, Giovanni Marsicano, Ismael Galve-Roperh, Luigi Bellocchio, Manuel Guzmán
The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D1 receptor (D1R-MSNs), and the indirect pathway, expressing dopamine D2 receptor (D2R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D1R-MSNs or D2R-MSNs remain unknown...
October 31, 2017: Cerebral Cortex
Jonathon Hull, Marcela Usmari Moraes, Emma Brookes, Seth Love, Myra E Conway
Glutamate is the major excitatory neurotransmitter of the central nervous system, with the branched-chain amino acids (BCAAs) acting as key nitrogen donors for de novo glutamate synthesis. Despite the importance of these major metabolites, their metabolic pathway in the human brain is still not well characterised. The metabolic pathways that influence the metabolism of BCAAs have been well characterised in rat models. However, the expression of key proteins such as the branched-chain α-ketoacid dehydrogenase (BCKD) complex and glutamate dehydrogenase isozymes (GDH) in the human brain is still not well characterised...
January 2018: Neurochemistry International
Jui-Yen Huang, Marisha Lynn Miskus, Hui-Chen Lu
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that Fgfr1/2/3 and Fgf7/9/10/22 mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs)...
December 13, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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