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Hillary C Schiff, Joshua P Johansen, Mian Hou, David Ea Bush, Emily K Smith, JoAnna E Klein, Joseph E LeDoux, Robert M Sears
Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on β-adrenergic receptors (βARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms...
October 20, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Bandhan Mukherjee, Qi Yuan
The interactions of L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) in memories are poorly understood. Here we investigated the specific roles of anterior piriform cortex (aPC) LTCCs and NMDARs in early odor preference memory in mice. Using calcium imaging in aPC slices, LTCC activation was shown to be dependent on NMDAR activation. Either D-APV (NMDAR antagonist) or nifedipine (LTCC antagonist) reduced somatic calcium transients in pyramidal cells evoked by lateral olfactory tract stimulation. However, nifedipine did not further reduce calcium in the presence of D-APV...
October 14, 2016: Scientific Reports
Daniel P Radin, Sheng Zhong, Richard Purcell, Arnold Lippa
Memory loss observed as a consequence of aging is paralleled by a down-regulation of AMPA-type glutamate receptors (AMPARs) that mediate fast excitatory synaptic transmission. Activation of these receptors enhances long-term potentiation (LTP), a neuronal process demonstrated to be crucial for memory storage and thought to be a cellular substrate of learning and memory. In the present studies, we determined that LTP was reduced in aged rats when compared to young rats and that acute treatment with CX1846, a novel AMPAR positive allosteric modulator, fifteen minutes prior to tetanic stimulation completely reversed the significant deficit in LTP observed in aged rats...
October 6, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Niels R Reinders, Yvonne Pao, Maria C Renner, Carla M da Silva-Matos, Tessa R Lodder, Roberto Malinow, Helmut W Kessels
Amyloid-β (Aβ) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer's disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aβ degrade synapses and impair memory formation. We show that all Aβ-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aβ-mediated synaptic depression and spine loss. In addition, Aβ oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xia Mao, Xinglong Gu, Wei Lu
GSG1L is an AMPA receptor (AMPAR) auxiliary subunit that regulates AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its physiological roles in other types of neurons remain to be characterized. Here we investigated the role of GSG1L in hippocampal dentate granule cells, and found that GSG1L is important for the regulation of synaptic strength, but is not critical for the modulation of AMPAR deactivation and desensitization kinetics. These data demonstrate a neuronal type-specific role of GSG1L and suggest that physiological function of AMPAR auxiliary subunits may vary in different types of neurons...
October 5, 2016: Journal of Neurophysiology
Andrei Rozov, Nail Burnashev
Suppression of NMDA receptor (NMDAR)-mediated currents by intracellular Ca(2+) has been described as a negative feedback loop in NMDAR modulation. In the time scale of tenths of milliseconds the depth of the suppression does not depend on the Ca(2+) source. It may be caused by Ca(2+) influx through voltage-gated calcium channels, NMDAR channels or release from intracellular stores. However, NMDARs are often co-expressed in synapses with Ca(2+)-permeable AMPA receptors (AMPARs). Due to significant differences in activation kinetics between these two types of glutamate receptors (GluRs), Ca(2+) entry through AMPARs precedes full activation of NMDARs, and therefore, might have an impact on the amplitude of NMDAR-mediated currents...
September 28, 2016: Cell Calcium
Cheryl Clarkson, Flora M Antunes, Maria E Rubio
UNLABELLED: Sound deprivation by conductive hearing loss increases hearing thresholds, but little is known about the response of the auditory brainstem during and after conductive hearing loss. Here, we show in young adult rats that 10 d of monaural conductive hearing loss (i.e., earplugging) leads to hearing deficits that persist after sound levels are restored. Hearing thresholds in response to clicks and frequencies higher than 8 kHz remain increased after a 10 d recovery period. Neural output from the cochlear nucleus measured at 10 dB above threshold is reduced and followed by an overcompensation at the level of the lateral lemniscus...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Iaroslav Savtchouk, Lu Sun, Crhistian L Bender, Qian Yang, Gábor Szabó, Sonia Gasparini, Siqiong June Liu
Synaptic receptors gate the neuronal response to incoming signals, but they are not homogeneously distributed on dendrites. A spatially defined receptor distribution can preferentially amplify certain synaptic inputs, resize receptive fields of neurons, and optimize information processing within a neuronal circuit. Thus, a longstanding question is how the spatial organization of synaptic receptors is achieved. Here, we find that action potentials provide local signals that influence the distribution of synaptic AMPA receptors along dendrites in mouse cerebellar stellate cells...
September 27, 2016: Cell Reports
Joongkyu Park, Andrés E Chávez, Yann S Mineur, Megumi Morimoto-Tomita, Stefano Lutzu, Kwang S Kim, Marina R Picciotto, Pablo E Castillo, Susumu Tomita
Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive...
October 5, 2016: Neuron
Valeria Zampini, Jian K Liu, Marco A Diana, Paloma P Maldonado, Nicolas Brunel, Stéphane Dieudonné
Synaptic currents display a large degree of heterogeneity of their temporal characteristics, but the functional role of such heterogeneities remains unknown. We investigated in rat cerebellar slices synaptic currents in Unipolar Brush Cells (UBCs), which generate intrinsic mossy fibers relaying vestibular inputs to the cerebellar cortex. We show that UBCs respond to sinusoidal modulations of their sensory input with heterogeneous amplitudes and phase shifts. Experiments and modeling indicate that this variability results both from the kinetics of synaptic glutamate transients and from the diversity of postsynaptic receptors...
September 19, 2016: ELife
Johan-Till Pougnet, Benjamin Compans, Audrey Martinez, Daniel Choquet, Eric Hosy, Eric Boué-Grabot
Plasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4...
2016: Scientific Reports
Lisa A Briand, Andre U Deutschmann, Alexandra S Ellis, Anne Q Fosnocht
Addiction is associated with changes in synaptic plasticity mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors at synapses within the nucleus accumbens. Exposure to cocaine can lead to protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and this phosphorylation event leads to the internalization of GluA2-containing AMPARs, which are calcium-impermeable. However, it is not clear whether this internalization is necessary for the expression of addictive phenotypes...
December 2016: Neuropharmacology
Pasha Ghazal
: It is now established that iteration of memory circuits takes place from hippocampus to cortical regions. The recall of recent event is largely dependent on the hippocampus networks, however, with passage of time, the cortical regions become largely involved in the recall of remote events. Molecular events, specifically, the AMPA receptor regulation underlying this iteration remains largely elusive. METHOD: Separate groups of mice were fear conditioned using contextual fear conditioning paradigm...
November 1, 2016: Brain Research
Roy S Song, Rosa Tolentino, Eric A Sobie, Susana R Neves-Zaph
Dopamine (DA), a key striatal neuromodulator, increases synaptic strength by promoting membrane insertion and/or retention of α-amino-3-hydroxy- 5-methyl- 4-isoxazolepropionic acid receptors (AMPARs). This process is mediated by GluA1-AMPAR subunit phosphorylation by cyclic nucleotide signaling, making cyclic nucleotide phosphodiesterases (PDEs) potential regulators of synaptic strength. In the current study we examined the role of phosphodiesterase-2 (PDE2), a medium spiny neurons (MSNs)-enriched and cGMP-activated PDE, in AMPAR trafficking...
September 7, 2016: Journal of Biological Chemistry
Xue-Yan He, Yan-Jun Li, Chakrapani Kalyanaraman, Li-Li Qiu, Chen Chen, Qi Xiao, Wen-Xue Liu, Wei Zhang, Jian-Jun Yang, Guiquan Chen, Matthew P Jacobson, Yun Stone Shi
AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in full-length GluA1/A2, aiming to draw the heteromeric AMPAR architecture...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Magali H Arons, Kevin Lee, Charlotte J Thynne, Sally A Kim, Claudia Schob, Stefan Kindler, Johanna M Montgomery, Craig C Garner
UNLABELLED: Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Bo Zhang, Thomas C Südhof
UNLABELLED: Neuroligins are postsynaptic cell-adhesion molecules that contribute to synapse specification. However, many other postsynaptic cell-adhesion molecules are known and the relative contributions of neuroligins versus other such molecules in different types of synapses and neurons remains largely unknown. Here, we have studied the role of neuroligins in cerebellar stellate interneurons that participate in a well defined circuit that converges on Purkinje cells as the major output neurons of cerebellar cortex...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Nese Sinmaz, Tina Nguyen, Fiona Tea, Russell C Dale, Fabienne Brilot
BACKGROUND: Our knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of extracellular and intracellular autoantigens have been identified, and there is no doubt that this field will continue to expand as more autoantigens are discovered as a result of improved clinical awareness and methodological practice. In recent years, interest has shifted to uncover the target epitopes of these autoantibodies...
2016: Journal of Neuroinflammation
Celine C Steinmetz, Vedakumar Tatavarty, Ken Sugino, Yasuyuki Shima, Anne Joseph, Heather Lin, Michael Rutlin, Mary Lambo, Chris M Hempel, Benjamin W Okaty, Suzanne Paradis, Sacha B Nelson, Gina G Turrigiano
Synaptic scaling is a form of homeostatic plasticity driven by transcription-dependent changes in AMPA-type glutamate receptor (AMPAR) trafficking. To uncover the pathways involved, we performed a cell-type-specific screen for transcripts persistently altered during scaling, which identified the μ subunit (μ3A) of the adaptor protein complex AP-3A. Synaptic scaling increased μ3A (but not other AP-3 subunits) in pyramidal neurons and redistributed dendritic μ3A and AMPAR to recycling endosomes (REs). Knockdown of μ3A prevented synaptic scaling and this redistribution, while overexpression (OE) of full-length μ3A or a truncated μ3A that cannot interact with the AP-3A complex was sufficient to drive AMPAR to REs...
September 6, 2016: Cell Reports
Garry Whitehead, Philip Regan, Daniel J Whitcomb, Kwangwook Cho
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the primary conduits of excitatory synaptic transmission. AMPARs are predominantly Ca(2+)-impermeable in the matured excitatory synapse, except under certain circumstances. Growing evidence implicates the Ca(2+) permeability of AMPARs in the regulation of long-term synaptic plasticity and in the pathophysiology of several neurological disorders. Therefore, the Ca(2+) conductance of AMPARs may have both physiological and pathological roles at synapses...
August 22, 2016: Neuropharmacology
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