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Signaling from the synapse to the nucleus and back to the synapse
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Abstracts / Neuroscience Research 68S (2010) e4–e52
NR2B trafficking and binding to the PSD-95 family of proteins. We also find that NR2B phosphorylation affects the balance of NR2A and NR2B expression at synapses. At the meeting, we will discuss our recent findings in the context of activity-dependent plasticity at synapses. doi:10.1016/j.neures.2010.07.272
S1-5-1-3 The consequences of chronic activity and inactivity on neuronal form and function Roger Nicoll , Carleton P. Goold, Wei Lu Department of Cellular and Molecular Pharmacology, UCSF A central issue in neurobiology is that, while neurons survive for the lifetime of an animal, their proteins (ion channels, neurotransmitter receptors, signaling molecules, etc.) are constantly turning over. Thus a neuron is continually rebuilding itself and this process is finely regulated both by genetic programs and the ongoing synaptic inputs that allows a neuron to maintain it activity within a narrow window. In brief, how much of a neuronal phenotype is determined by intrinsic genetic programs versus activity? To determine the role that activity plays in sculpting the electrophysiological and structural signature of a neuron, we have used two perturbations. First, we have deleted AMPA and NMDA receptors in single pyramidal cells and secondly we have chronically stimulated individual neurons with an optogenetic approach. The consequences of these two manipulations will be the basis of my talk. doi:10.1016/j.neures.2010.07.273
S1-5-1-4 AMPA receptor auxiliary subunits to specify neuropharmacology and synapticplasticity David Bredt , Akihiko S. Kato, Martin B. Gill Neuroscience Discovery and Clinical Investigation, Eli Lilly Transmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel and are conserved across the animal kingdom. While initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent work demonstrated that it also regulates AMPA receptor kineticsand synaptic waveforms. Further analyses identified a diverse collection of TARP isoforms (types Ia, Ib, II) that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. More recent studies have defined cornichon (CNIH2/3) and CKAMP44 proteins as additional AMPA receptor subunits. Our study characterizes interactions amongst these distinct classes of transmembrane AMPA receptor associated proteins to understand how they cooperate to regulate synaptic transmission in distinct neuronal types. doi:10.1016/j.neures.2010.07.274
S1-5-1-5 Establishment and function of postsynaptic signaling complexes Andres Villu Maricq Department of Biology, University of Utah Experience-dependent changes in the properties and numbers of postsynaptic ionotropic glutamate receptors (iGluRs) are considered to be of central importance for learning and memory. Until rather recently iGluRs were thought to function as stand-alone receptors. However, recent studies from a number of laboratories have challenged this notion. It is now well established that the AMPA subtype of iGluR (AMPAR) is part of a multi-protein receptor complex. To find additional proteins that contribute to iGluR function, we used a forward genetic approach in C. elegans. We identified SOL-2, a new gene product that co-localizes with the GLR-1 iGluR. We will discuss how SOL-2 contributes to glutamatergic signaling mediated by AMPARs. doi:10.1016/j.neures.2010.07.275
S1-5-1-6 Signaling from the synapse to the nucleus and back to the synapse Haruhiko Bito , Takashi Kawashima, Masatoshi Inoue, Nan Yagishita-Kyo, Mio Nonaka, Hajime Fujii, Hiroyuki Okuno Dept Neurochem, Univ of Tokyo Grad Sch Med, Tokyo Induction and expression synaptic plasticity at glutamatergic synapses are thought to underlie formation of new memory in many area of the brain. Furthermore, for a new memory to be consolidated and for plasticity to persist, new protein synthesis is required. However, the mechanism by which
heightened glutamatergic transmission can trigger synthesis of new mRNA in the nucleus is not fully understood. Similarly, we know very little about how the translation products of these new transcripts may be appropriately targeted to their final destination inside a stimulated neuron. We will present data from ongoing studies that aim to understand the complete signal transduction cascade originating from synaptic NMDA receptors and leading to activation of the immediate early gene Arc via nuclear CREB activation. We will also present new evidence indicating that the accumulation of an activity-regulated synaptic gene product may depend on the immediate history of synaptic activity at its target synapse site. The molecular basis of this activity-based targeting process is being investigated. doi:10.1016/j.neures.2010.07.276
S1-5-2-1 How studies of motor learning and effects of brain stimulation in animal and human models may contribute to more effective neurorehabilitative strategies Leonardo Cohen NINDS, NIH Neurorehabilitation has seen an important development in the last decade. Basic science animal studies demonstrated that it is possible to evaluate the mechanisms underlying learning and relearning after brain lesions. These studies started to generate exciting information that over the last few years became increasingly important in the design of novel rehabilitative strategies in humans. Importantly, data from clinical studies started to influence the design of animal studies. Human studies in healthy volunteers allowed the formulation of hypothesis on motor rehabilitation applicable to neurorehabilitation following stroke and allowed partial optimization of interventional approaches. More recently, human studies on the effects of invasive and noninvasive brain stimulation unveiled the possibility of facilitating training effects. Thus, different forms of brain stimulation are now known to facilitate motor performance and motor skill learning. The mechanisms underlying these effects are under investigation. It is likely that information on the now more fluid interaction between studies designed in animals and humans and their influence in the development of neurorehabilitative protocols following brain injury will improve the development of treatment options. doi:10.1016/j.neures.2010.07.277
S1-5-2-2 Quadripulse transcranial magnetic stimulation can produce neuroplasticity Setsu Nakatani-Enomoto , Yoshikazu Ugawa Department of Neurology, School of Medicine, Fukushima Medical University Quadripulse transcranial magnetic stimulation (QPS) is one kind of new patterned repetitive transcranial magnetic stimulation (rTMS) methods introduced by Hamada et al. in 2007. In this method, one train consists of four monophasic TMS pulses. The inter-stimulus interval (ISI) between successive pulses was set from 1.5 to 1250 ms. The inter-train interval was set at 5 s. One session contained 360 trains for 30 min at the same intensity of 90% active motor threshold. (1) Effects on the primary motor cortex (M1) motor evoked potentials (MEPs) were recorded before and after QPS applied over M1 from first dorsal interosseus muscle. MEPs were enlarged after QPS at short ISIs of 1.5, 5, 10 ms and diminished by QPS at long ISIs of 30, 50, 100, 1250 ms (5 ms = QPS-5 and 50 ms = QPS-50 for more than 75 min, the best). Neither the motor thresholds nor short-interval intracortical inhibition was affected by any QPSs. The relation between the degree of M1 plastic changes and the QPS inter-stimulus interval corresponded to the Bienenstock–Cooper–Munro theory. (2) Effects on the sensory cortex median nerve somatosensory evoked potentials (SEPs) were recorded before and after QPS. QPS-5 over M1 enhanced the P25/N33 component and QPS-50 over M1 reduced it without any changes in other components. QPS-5 over the premotor cortex (PM) enhanced the P25/N33 component whereas QPS50 over PM did not affect SEPs. In contrast, QPS over the sensory cortex had no influence on any components of SEP. The physiological characteristics of QPS induced effect on M1 are all consistent with the synaptic plasticity shown in animals. The sensory cortex is also similarly modulated by QPS over M1. QPS is one of the promising methods for inducing LTP and LTD-like plasticity in humans. This enables us to examine metaplasticity theory in more details in humans. QPS might be also useful to induce symptomatic relief in patients with neurological or psychiatric disorders. doi:10.1016/j.neures.2010.07.278
Abstracts / Neuroscience Research 68S (2010) e4–e52
NR2B trafficking and binding to the PSD-95 family of proteins. We also find that NR2B phosphorylation affects the balance of NR2A and NR2B expression at synapses. At the meeting, we will discuss our recent findings in the context of activity-dependent plasticity at synapses. doi:10.1016/j.neures.2010.07.272
S1-5-1-3 The consequences of chronic activity and inactivity on neuronal form and function Roger Nicoll , Carleton P. Goold, Wei Lu Department of Cellular and Molecular Pharmacology, UCSF A central issue in neurobiology is that, while neurons survive for the lifetime of an animal, their proteins (ion channels, neurotransmitter receptors, signaling molecules, etc.) are constantly turning over. Thus a neuron is continually rebuilding itself and this process is finely regulated both by genetic programs and the ongoing synaptic inputs that allows a neuron to maintain it activity within a narrow window. In brief, how much of a neuronal phenotype is determined by intrinsic genetic programs versus activity? To determine the role that activity plays in sculpting the electrophysiological and structural signature of a neuron, we have used two perturbations. First, we have deleted AMPA and NMDA receptors in single pyramidal cells and secondly we have chronically stimulated individual neurons with an optogenetic approach. The consequences of these two manipulations will be the basis of my talk. doi:10.1016/j.neures.2010.07.273
S1-5-1-4 AMPA receptor auxiliary subunits to specify neuropharmacology and synapticplasticity David Bredt , Akihiko S. Kato, Martin B. Gill Neuroscience Discovery and Clinical Investigation, Eli Lilly Transmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel and are conserved across the animal kingdom. While initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent work demonstrated that it also regulates AMPA receptor kineticsand synaptic waveforms. Further analyses identified a diverse collection of TARP isoforms (types Ia, Ib, II) that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. More recent studies have defined cornichon (CNIH2/3) and CKAMP44 proteins as additional AMPA receptor subunits. Our study characterizes interactions amongst these distinct classes of transmembrane AMPA receptor associated proteins to understand how they cooperate to regulate synaptic transmission in distinct neuronal types. doi:10.1016/j.neures.2010.07.274
S1-5-1-5 Establishment and function of postsynaptic signaling complexes Andres Villu Maricq Department of Biology, University of Utah Experience-dependent changes in the properties and numbers of postsynaptic ionotropic glutamate receptors (iGluRs) are considered to be of central importance for learning and memory. Until rather recently iGluRs were thought to function as stand-alone receptors. However, recent studies from a number of laboratories have challenged this notion. It is now well established that the AMPA subtype of iGluR (AMPAR) is part of a multi-protein receptor complex. To find additional proteins that contribute to iGluR function, we used a forward genetic approach in C. elegans. We identified SOL-2, a new gene product that co-localizes with the GLR-1 iGluR. We will discuss how SOL-2 contributes to glutamatergic signaling mediated by AMPARs. doi:10.1016/j.neures.2010.07.275
S1-5-1-6 Signaling from the synapse to the nucleus and back to the synapse Haruhiko Bito , Takashi Kawashima, Masatoshi Inoue, Nan Yagishita-Kyo, Mio Nonaka, Hajime Fujii, Hiroyuki Okuno Dept Neurochem, Univ of Tokyo Grad Sch Med, Tokyo Induction and expression synaptic plasticity at glutamatergic synapses are thought to underlie formation of new memory in many area of the brain. Furthermore, for a new memory to be consolidated and for plasticity to persist, new protein synthesis is required. However, the mechanism by which
heightened glutamatergic transmission can trigger synthesis of new mRNA in the nucleus is not fully understood. Similarly, we know very little about how the translation products of these new transcripts may be appropriately targeted to their final destination inside a stimulated neuron. We will present data from ongoing studies that aim to understand the complete signal transduction cascade originating from synaptic NMDA receptors and leading to activation of the immediate early gene Arc via nuclear CREB activation. We will also present new evidence indicating that the accumulation of an activity-regulated synaptic gene product may depend on the immediate history of synaptic activity at its target synapse site. The molecular basis of this activity-based targeting process is being investigated. doi:10.1016/j.neures.2010.07.276
S1-5-2-1 How studies of motor learning and effects of brain stimulation in animal and human models may contribute to more effective neurorehabilitative strategies Leonardo Cohen NINDS, NIH Neurorehabilitation has seen an important development in the last decade. Basic science animal studies demonstrated that it is possible to evaluate the mechanisms underlying learning and relearning after brain lesions. These studies started to generate exciting information that over the last few years became increasingly important in the design of novel rehabilitative strategies in humans. Importantly, data from clinical studies started to influence the design of animal studies. Human studies in healthy volunteers allowed the formulation of hypothesis on motor rehabilitation applicable to neurorehabilitation following stroke and allowed partial optimization of interventional approaches. More recently, human studies on the effects of invasive and noninvasive brain stimulation unveiled the possibility of facilitating training effects. Thus, different forms of brain stimulation are now known to facilitate motor performance and motor skill learning. The mechanisms underlying these effects are under investigation. It is likely that information on the now more fluid interaction between studies designed in animals and humans and their influence in the development of neurorehabilitative protocols following brain injury will improve the development of treatment options. doi:10.1016/j.neures.2010.07.277
S1-5-2-2 Quadripulse transcranial magnetic stimulation can produce neuroplasticity Setsu Nakatani-Enomoto , Yoshikazu Ugawa Department of Neurology, School of Medicine, Fukushima Medical University Quadripulse transcranial magnetic stimulation (QPS) is one kind of new patterned repetitive transcranial magnetic stimulation (rTMS) methods introduced by Hamada et al. in 2007. In this method, one train consists of four monophasic TMS pulses. The inter-stimulus interval (ISI) between successive pulses was set from 1.5 to 1250 ms. The inter-train interval was set at 5 s. One session contained 360 trains for 30 min at the same intensity of 90% active motor threshold. (1) Effects on the primary motor cortex (M1) motor evoked potentials (MEPs) were recorded before and after QPS applied over M1 from first dorsal interosseus muscle. MEPs were enlarged after QPS at short ISIs of 1.5, 5, 10 ms and diminished by QPS at long ISIs of 30, 50, 100, 1250 ms (5 ms = QPS-5 and 50 ms = QPS-50 for more than 75 min, the best). Neither the motor thresholds nor short-interval intracortical inhibition was affected by any QPSs. The relation between the degree of M1 plastic changes and the QPS inter-stimulus interval corresponded to the Bienenstock–Cooper–Munro theory. (2) Effects on the sensory cortex median nerve somatosensory evoked potentials (SEPs) were recorded before and after QPS. QPS-5 over M1 enhanced the P25/N33 component and QPS-50 over M1 reduced it without any changes in other components. QPS-5 over the premotor cortex (PM) enhanced the P25/N33 component whereas QPS50 over PM did not affect SEPs. In contrast, QPS over the sensory cortex had no influence on any components of SEP. The physiological characteristics of QPS induced effect on M1 are all consistent with the synaptic plasticity shown in animals. The sensory cortex is also similarly modulated by QPS over M1. QPS is one of the promising methods for inducing LTP and LTD-like plasticity in humans. This enables us to examine metaplasticity theory in more details in humans. QPS might be also useful to induce symptomatic relief in patients with neurological or psychiatric disorders. doi:10.1016/j.neures.2010.07.278