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Megumi Taketo, Hiroko Matsuda
Activity-dependent plasticity including short and long-term depression accompanied by a reduction in transmitter release probability has been demonstrated in both inhibitory and excitatory synapses. In the neonatal hippocampus, repetitive postsynaptic depolarization is followed by presynaptic alterations of the efficacy of GABAAergic transmission. Both facilitation and inhibition have been observed, but the mechanisms underlying this plasticity have not yet been elucidated. In the present experiment, repetitive postsynaptic depolarization by itself did not cause marked alterations of spontaneous inhibitory postsynaptic currents (sIPSCs)...
April 15, 2017: Neuropharmacology
M J Ramaker, S C Dulawa
Depression is a leading cause of disability worldwide and a major contributor to the burden of suicide. A major limitation of classical antidepressants is that 2-4 weeks of continuous treatment is required to elicit therapeutic effects, prolonging the period of depression, disability and suicide risk. Therefore, the development of fast-onset antidepressants is crucial. Preclinical identification of fast-onset antidepressants requires animal models that can accurately predict the delay to therapeutic onset. Although several well-validated assay models exist that predict antidepressant potential, few thoroughly tested animal models exist that can detect therapeutic onset...
March 21, 2017: Molecular Psychiatry
M Sgritta, F Locatelli, T Soda, F Prestori, E D'Angelo
Spike-timing dependent plasticity (STDP) is a form of long-term synaptic plasticity exploiting the time relationship between postsynaptic action potentials (AP) and EPSPs. Surprisingly enough, very little was known about STDP in the cerebellum, although it is thought to play a critical role for learning appropriate timing of actions. We speculated that low-frequency oscillations observed in the granular layer may provide a reference for repetitive EPSP/AP phase coupling. Here we show that EPSP-spike pairing at 6Hz can optimally induce STDP at the mossy fiber - granule cell synapse in rats...
February 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Elizabeth Nicholson, Dimitri M Kullmann
KEY POINTS: Regular-spiking interneurons in the hippocampal stratum oriens exhibit a form of long-term potentiation of excitatory transmission that is independent of NMDA receptors but requires co-activation of Ca(2+) -permeable AMPA receptors and group I metabotropic glutamate receptors. We show that T-type Ca(2+) channels are present in such interneurons. Blockade of T-type currents prevents the induction of long-term potentiation, and also interferes with long-lasting potentiation induced either by postsynaptic trains of action potentials or by pairing postsynaptic hyperpolarization with activation of group I metabotropic receptors...
January 30, 2017: Journal of Physiology
Jae Young Yoon, Sukwoo Choi
Silent synapses show NMDA receptor (NMDAR)-mediated synaptic responses, but not AMPAR-mediated synaptic responses. A prevailing hypothesis states that silent synapses contain NMDARs, but not AMPARs. However, alternative presynaptic hypotheses, according to which AMPARs are present at silent synapses, have been proposed; silent synapses show slow glutamate release via a fusion pore, and glutamate spillover from the neighboring synaptic terminals. Consistent with these presynaptic hypotheses, the peak glutamate concentrations at silent synapses have been estimated to be ≪170 μM, much lower than those seen at functional synapses...
January 22, 2017: Biochemical and Biophysical Research Communications
Ioline D Henter, Rafael T de Sousa, Philip W Gold, Andre R Brunoni, Carlos A Zarate, Rodrigo Machado-Vieira
Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders. Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators...
February 2017: Expert Review of Clinical Pharmacology
S Y Yau, C A Bostrom, J Chiu, C J Fontaine, S Sawchuk, A Meconi, R C Wortman, E Truesdell, A Truesdell, C Chiu, B N Hryciw, B D Eadie, M Ghilan, B R Christie
Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits...
September 19, 2016: Neurobiology of Disease
Christine Gebhardt, Oliver von Bohlen Und Halbach, Michael D Hadler, Christian Harteneck, Doris Albrecht
Recently we have shown that capsaicin attenuates the strength of LTP in the lateral amygdala (LA) and demonstrated that this effect is mediated by the transient receptor potential (TRP) channel TRPV1. Here we further show that capsaicin, which is thought to act primarily through TRPV1, modifies long term depression (LTD) in the LA. Yet the application of various TRPV1 antagonists does not reverse this effect and it remains in TRPV1-deficient mice. In addition, voltage gated calcium channels, nitric oxide and CB1 receptors are not involved...
December 2016: Neurobiology of Learning and Memory
Zhong-Feng Wang, Xiong-Li Yang
Glaucoma, the second leading cause of blindness, is a neurodegenerative disease characterized by optic nerve degeneration related to apoptotic death of retinal ganglion cells (RGCs). In the pathogenesis of RGC death following the onset of glaucoma, functional changes of glutamate receptors are commonly regarded as important risk factors. During the past several years, we have explored the mechanisms underlying RGC apoptosis and retinal Müller cell reactivation (gliosis) in a rat chronic ocular hypertension (COH) model...
August 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Venkat Swaroop Achuta, Heli Grym, Noora Putkonen, Verna Louhivuori, Virve Kärkkäinen, Jari Koistinaho, Laurent Roybon, Maija L Castrén
Disrupted metabotropic glutamate receptor 5 (mGluR5) signaling is implicated in many neuropsychiatric disorders, including autism spectrum disorder, found in fragile X syndrome (FXS). Here we report that intracellular calcium responses to the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) are augmented, and calcium-dependent mGluR5-mediated mechanisms alter the differentiation of neural progenitors in neurospheres derived from human induced pluripotent FXS stem cells and the brains of mouse model of FXS...
April 2017: Developmental Neurobiology
Xiao-xiao Li, Sheng-feng Lu, Bing-mei Zhu, Shu-ping Fu
Excitatory amino acids toxicity is an onset causation of cerebral ischemia injury cascade reaction, and eventually leading to brain cell necrosis and apoptosis. Acupuncture is reported to be effective for ischemic stroke in clinical practice and animal experiments, but its mechanism is still under exploring. In this paper the authors introduce the research status of antiexcitatory amino acids toxicity effect of acupuncture in ischemic stroke animals by summarizing its effects on subunits of ionotropic glutamate receptor (NMDA/AMPA) and metabotropic glutamate receptors (mGluRs), and on astrocyte activities...
April 2016: Zhen Ci Yan Jiu, Acupuncture Research
Stephen Fitzjohn, Zafar Bashir, Paul Farrow
NMDA receptors are composed of multiple subunits and are crucial in the induction of synaptic plasticity and learning and memory. In this study, application of the group I mGlu receptor agonist, DHPG, caused LTD of NMDA-EPSCs (DHPG-LTDNMDA) of the Schaffer collateral, but not of NMDA-EPSCs of the temperoammonic pathway onto CA1 neurons of the hippocampus. DHPGLTDNMDA did not alter the sensitivity of NMDA-EPSC to the GluN2B-antagonist, Ro25-6981, indicating that the postsynaptic NMDA receptor subunit composition remained unchanged following DHPG-LTDNMDA...
2016: Current Neuropharmacology
Brittany A Jaso, Mark J Niciu, Nicolas D Iadarola, Niall Lally, Erica M Richards, Minkyung Park, Elizabeth D Ballard, Allison C Nugent, Rodrigo Machado-Vieira, Carlos A Zarate
Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and realworld effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder...
2017: Current Neuropharmacology
Hui Wang, Alvaro O Ardiles, Sunggu Yang, Trinh Tran, Rafael Posada-Duque, Gonzalo Valdivia, Min Baek, Yang-An Chuang, Adrian G Palacios, Michela Gallagher, Paul Worley, Alfredo Kirkwood
UNLABELLED: Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification...
February 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Noriomi Eguchi, Akitoyo Hishimoto, Ichiro Sora, Masahiro Mori
Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of -70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors...
March 11, 2016: Neuroscience Letters
Minkyung Park, Mark J Niciu, Carlos A Zarate
All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Here, we review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and the group I, II, and III metabotropic glutamate receptors (mGluRs)-in the development of novel and more effective treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors...
December 2015: Current Behavioral Neuroscience Reports
Beata Dąbrowska-Bouta, Lidia Strużyńska, Małgorzata Chalimoniuk, Małgorzata Frontczak-Baniewicz, Grzegorz Sulkowski
Elevated extracellular glutamate in the synaptic cleft causes overactivation of glutamate receptors and kills neurons by an excitotoxic mechanism. Recent studies have shown that glutamate can also lead to toxic injury of white matter oligodendrocytes in myelin sheaths and consequently to axon demyelination. The present study was performed using the rodent model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE). The aim of the study was to test the effects of the glutamatergic receptor antagonists amantadine and memantine (antagonists of NMDA receptors), LY 367384 (an antagonist of mGluR1), and MPEP (an mGluR5 antagonist) on the development of neurological symptoms in immunized animals, morphological changes in cerebral myelin, and expression of mRNA of the principal myelin proteins PLP, MBP, MOG, MAG, and CNPase...
2015: Folia Neuropathologica
Jun Ho Jang, Taick Sang Nam, Jaebeom Jun, Se Jung Jung, Dong-Wook Kim, Joong Woo Leem
We investigated the role of peripheral NMDA receptors (NMDARs) in antidromic nerve stimulation-induced tactile hypersensitivity outside the skin area innervated by stimulated nerve. Tetanic electrical stimulation (ES) of the decentralized L5 spinal nerve, which induced enlargement of plasma extravasation, resulted in tactile hypersensitivity in the L4 plantar dermatome of the hind-paw. When intraplantar ( injection was administered into the L4 dermatome before ES, NMDAR and group-I metabotropic Glu receptor (mGluR) antagonists and group-II mGluR agonist but not AMPA/kainate receptor antagonist prevented ES-induced hypersensitivity...
2015: Mediators of Inflammation
S A Neymotin, R A McDougal, A S Bulanova, M Zeki, P Lakatos, D Terman, M L Hines, W W Lytton
Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca(2+)) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors...
March 1, 2016: Neuroscience
Rodrigo Machado-Vieira, Ioline D Henter, Carlos A Zarate
Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder...
December 23, 2015: Progress in Neurobiology
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