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Michael Ohene-Nyako, Amanda L Persons, T Celeste Napier
Methamphetamine abuse co-occurring with HIV infection presents neuropathology in brain regions that mediate reward and motivation. A neuronal signaling cascade altered acutely by meth and some HIV-1 proteins is the mitogen-activated protein kinase (MAPK) pathway. It remains unknown if chronic co-exposure to meth and HIV-1 proteins converge on MAPK in vivo. To make this determination, we studied young adult Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats that self-administered meth (0.02-0.04 mg/kg/0.05 ml iv infusion, 2 h/day for 21 days) and their saline-yoked controls...
June 21, 2018: Brain Structure & Function
Sami El-Boustani, Jacque P K Ip, Vincent Breton-Provencher, Graham W Knott, Hiroyuki Okuno, Haruhiko Bito, Mriganka Sur
Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but the manner in which different forms of synaptic plasticity act together to create functional changes in neurons remains unknown. We found that spike timing-induced receptive field plasticity of visual cortex neurons in mice is anchored by increases in the synaptic strength of identified spines. This is accompanied by a decrease in the strength of adjacent spines on a slower time scale. The locally coordinated potentiation and depression of spines involves prominent AMPA receptor redistribution via targeted expression of the immediate early gene product Arc...
June 22, 2018: Science
Rafael Falcón-Moya, Pilar Losada-Ruiz, Talvinder S Sihra, Antonio Rodríguez-Moreno
We elucidated the mechanisms underlying the kainate receptor (KAR)-mediated facilitatory modulation of synaptic transmission in the cerebellum. In cerebellar slices, KA (3 μM) increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs) at synapses between axon terminals of parallel fibers (PF) and Purkinje neurons. KA-mediated facilitation was antagonized by NBQX under condition where AMPA receptors were previously antagonized. Inhibition of protein kinase A (PKA) suppressed the effect of KA on glutamate release, which was also obviated by the prior stimulation of adenylyl cyclase (AC)...
2018: Frontiers in Molecular Neuroscience
Theis H Ipsen, Filip S Polli, Kristi A Kohlmeier
Nicotine exposure during gestation is associated with a higher risk of adverse behavioral outcomes including a heightened liability for dependency to drugs of abuse, which can exhibit drug-specificity influenced by gender. This enhanced liability suggests that nicotine use during pregnancy alters neural development in circuits involved in motivation and reward learning. The ventral tegmental area (VTA) is critical in motivated behaviors and we hypothesized that gestational exposure to nicotine could alter the development of excitatory circuits in this nucleus...
June 20, 2018: Developmental Neurobiology
Coralie Berthoux, Alexander Barre, Joël Bockaert, Philippe Marin, Carine Bécamel
The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized...
June 16, 2018: Cerebral Cortex
Bo Am Seo, Taesup Cho, Daniel Z Lee, Joong-Jae Lee, Boyoung Lee, Seong-Wook Kim, Hee-Sup Shin, Myoung-Goo Kang
Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Maria Lisa Rossi, Gemma Rubbini, Marta Martini, Rita Canella, Riccardo Fesce
The role of glutamate in quantal release at the cytoneural junction was examined by measuring mEPSPs and afferent spikes at the posterior canal in the intact frog labyrinth. Release was enhanced by exogenous glutamate, or DL-TBOA, a blocker of glutamate reuptake. Conversely, drugs acting on ionotropic glutamate receptors did not affect release; the AMPA-R blocker CNQX decreased mEPSP size in a dose-dependent manner; the NMDA-R blocker D-AP5 at concentrations <200 µM did not affect mEPSP size, either in the presence or absence of Mg and glycine...
June 15, 2018: Neuroscience
Alessandro Tozzi, Valentina Durante, Guendalina Bastioli, Petra Mazzocchetti, Salvatore Novello, Alessandro Mechelli, Michele Morari, Cinzia Costa, Andrea Mancini, Massimiliano Di Filippo, Paolo Calabresi
Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice...
June 13, 2018: Neurobiology of Disease
Daniel P Radin, Yong-Xin Li, Gary Rogers, Richard Purcell, Arnold Lippa
Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation...
June 12, 2018: Biochemical Pharmacology
Eric Salter, Julia Sunstrum, Sara Matovic, Wataru Inoue
KEY POINTS: Glutamatergic synaptic inputs to corticotropin releasing hormone (CRH) secreting neurons in the paraventricular nucleus of the hypothalamus (PVN) are required for stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. These synapses also undergo stress-induced plasticity thereby influencing HPA axis stress adaptation. By using patch clamp electrophysiology, we show that, in adult non-stressed mice, action potentials at these glutamatergic afferents elicit multiquantal transmission to the postsynaptic PVN-CRH neurons (i...
June 14, 2018: Journal of Physiology
Ji-Woon Kim, Kwanghoon Park, Ri Jin Kang, Edson Luck T Gonzales, Do Gyeong Kim, Hyun Ah Oh, Hana Seung, Mee Jung Ko, Kyoung Ja Kwon, Ki Chan Kim, Sung Hoon Lee, ChiHye Chung, Chan Young Shin
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice...
May 22, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Shumpei Fujii, Hiromitsu Tanaka, Tomoo Hirano
The decrease in number of AMPA-type glutamate receptor (AMPAR) at excitatory synapses causes LTD, a cellular basis of learning and memory. The number of postsynaptic AMPARs is regulated by the balance of exocytosis and endocytosis, and enhanced endocytosis of AMPAR has been suggested to underlie the LTD expression. However, it remains unclear how endocytosis and exocytosis of AMPAR change during LTD. In this study, we addressed this question by analyzing exocytosis and endocytosis of AMPAR by imaging super-ecliptic pHlorin (SEP)-tagged AMPAR around postsynaptic structure formed directly on the glass surface in the hippocampal culture prepared from rat embryos of both sexes...
June 13, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Patricio Opazo, Silvia Viana da Silva, Mario Carta, Christelle Breillat, Steven J Coultrap, Dolors Grillo-Bosch, Matthieu Sainlos, Françoise Coussen, K Ulrich Bayer, Christophe Mulle, Daniel Choquet
Alzheimer's disease (AD) is emerging as a synaptopathology driven by metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the downstream Ca2+ -dependent signaling molecules that mediate aberrant metaplasticity are unknown. In this study, we show that oAβ promotes the activation of Ca2+ /calmodulin-dependent kinase II (CaMKII) via GluN2B-containing NMDARs...
June 12, 2018: Cell Reports
Yanrui Yang, Jiang Chen, Zhenzhen Guo, Shikun Deng, Xiangyang Du, Shaoxia Zhu, Chang Ye, Yun S Shi, Jia-Jia Liu
Endophilin A1 is a member of the N-BAR domain-containing endophilin A protein family that is involved in membrane dynamics and trafficking. At the presynaptic terminal, endophilin As participate in synaptic vesicle recycling and autophagosome formation. By gene knockout studies, here we report that postsynaptic endophilin A1 functions in synaptic plasticity. Ablation of endophilin A1 in the hippocampal CA1 region of mature mouse brain impairs long-term spatial and contextual fear memory. Its loss in CA1 neurons postsynaptic of the Schaffer collateral pathway causes impairment in their AMPA-type glutamate receptor-mediated synaptic transmission and long-term potentiation...
2018: Frontiers in Molecular Neuroscience
Lionel Froux, Morgane Le Bon-Jego, Cristina Miguelez, Elisabeth Normand, Stephanie Morin, Stéphanie Fioramonti, Massimo Barresi, Andreas Frick, Jerome Baufreton, Anne Taupignon
Corticofugal fibers target the subthalamic nucleus (STN), a component nucleus of the basal ganglia, in addition to the striatum, their main input. The cortico-subthalamic, or hyperdirect, pathway, is thought to supplement the cortico-striatal pathways in order to interrupt/change planned actions. To explore the previously unknown properties of the neurons that project to the STN, retrograde and anterograde tools were used to specifically identify them in the motor cortex and selectively stimulate their synapses in the STN...
June 11, 2018: Scientific Reports
Jiejie Wang, Xinyou Lv, Yu Wu, Tao Xu, Mingfei Jiao, Risheng Yang, Xia Li, Ming Chen, Yinggang Yan, Changwan Chen, Weifan Dong, Wei Yang, Min Zhuo, Tao Chen, Jianhong Luo, Shuang Qiu
NMDA receptors (NMDARs) are crucial for excitatory synaptic transmission and synaptic plasticity. The number and subunit composition of synaptic NMDARs are tightly controlled by neuronal activity and sensory experience, but the molecular mechanism mediating NMDAR trafficking remains poorly understood. Here, we report that RIM1, with a well-established role in presynaptic vesicle release, also localizes postsynaptically in the mouse hippocampus. Postsynaptic RIM1 in hippocampal CA1 region is required for basal NMDAR-, but not AMPA receptor (AMPAR)-, mediated synaptic responses, and contributes to synaptic plasticity and hippocampus-dependent memory...
June 11, 2018: Nature Communications
Alvin Yu, Albert Y Lau
At central nervous system synapses, agonist binding to postsynaptic ionotropic glutamate receptors (iGluRs) results in signaling between neurons. N-Methyl-D-aspartic acid (NMDA) receptors are a unique family of iGluRs that activate in response to the concurrent binding of glutamate and glycine. Here, we investigate the process of agonist binding to the GluN2A (glutamate binding) and GluN1 (glycine binding) NMDA receptor subtypes using long-timescale unbiased molecular dynamics simulations. We find that positively charged residues on the surface of the GluN2A ligand-binding domain (LBD) assist glutamate binding via a "guided-diffusion" mechanism, similar in fashion to glutamate binding to the GluA2 LBD of AMPA receptors...
May 23, 2018: Structure
Daniel P Radin, Steven Johnson, Richard Purcell, Arnold S Lippa
Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors...
June 6, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Carina Volk, Valeria Jaramillo, Renato Merki, Ruth O'Gorman Tuura, Reto Huber
The glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is involved in synaptic plasticity processes, and animal studies have demonstrated altered expression across the sleep wake cycle. Accordingly, glutamate levels are reduced during non-rapid eye movement (NREM) sleep and the rate of this decrease is positively correlated with sleep EEG slow wave activity (SWA). Here, we combined proton magnetic resonance spectroscopy (1 H-MRS) and high-density sleep EEG to assess if 1 H-MRS is sensitive to diurnal changes of glutamate + glutamine (GLX) in healthy young adults and if potential overnight changes of GLX are correlated to SWA...
June 8, 2018: Human Brain Mapping
Giri P Krishnan, Oscar C González, Maxim Bazhenov
Resting- or baseline-state low-frequency (0.01-0.2 Hz) brain activity is observed in fMRI, EEG, and local field potential recordings. These fluctuations were found to be correlated across brain regions and are thought to reflect neuronal activity fluctuations between functionally connected areas of the brain. However, the origin of these infra-slow resting-state fluctuations remains unknown. Here, using a detailed computational model of the brain network, we show that spontaneous infra-slow (<0.05 Hz) activity could originate due to the ion concentration dynamics...
June 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
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