Science.gov

Sample records for short-term synaptic plasticity

  1. Short-term synaptic plasticity and heterogeneity in neural systems

    NASA Astrophysics Data System (ADS)

    Mejias, J. F.; Kappen, H. J.; Longtin, A.; Torres, J. J.

    2013-01-01

    We review some recent results on neural dynamics and information processing which arise when considering several biophysical factors of interest, in particular, short-term synaptic plasticity and neural heterogeneity. The inclusion of short-term synaptic plasticity leads to enhanced long-term memory capacities, a higher robustness of memory to noise, and irregularity in the duration of the so-called up cortical states. On the other hand, considering some level of neural heterogeneity in neuron models allows neural systems to optimize information transmission in rate coding and temporal coding, two strategies commonly used by neurons to codify information in many brain areas. In all these studies, analytical approximations can be made to explain the underlying dynamics of these neural systems.

  2. The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

    ERIC Educational Resources Information Center

    Chandrasekaran, Lakshmi

    2008-01-01

    Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

  3. Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis

    PubMed Central

    Sanchez, Jason Tait; Quinones, Karla; Otto-Meyer, Sebastian

    2015-01-01

    Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM), an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired-pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca2+-dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R). Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM. PMID:26527054

  4. Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats.

    PubMed

    Stein, Liana R; O'Dell, Kazuko A; Funatsu, Michiyo; Zorumski, Charles F; Izumi, Yukitoshi

    2016-08-01

    Age-associated changes in cognition are mirrored by impairments in cellular models of memory and learning, such as long-term potentiation (LTP) and long-term depression (LTD). In young rodents, environmental enrichment (EE) can enhance memory, alter LTP and LTD, as well as reverse cognitive deficits induced by aging. Whether short-term EE can benefit cognition and synaptic plasticity in aged rodents is unclear. Here, we tested if short-term EE could overcome age-associated impairments in induction of LTP and LTD. LTP and LTD could not be induced in the CA1 region of hippocampal slices in control, aged rats using standard stimuli that are highly effective in young rats. However, exposure of aged littermates to EE for three weeks enabled successful induction of LTP and LTD. EE-facilitated LTP was dependent upon N-methyl-d-aspartate receptors (NMDARs). These alterations in synaptic plasticity occurred with elevated levels of phosphorylated cAMP response element-binding protein and vascular endothelial growth factor, but in the absence of changes in several other synaptic and cellular markers. Importantly, our study suggests that even a relatively short period of EE is sufficient to alter synaptic plasticity and molecular markers linked to cognitive function in aged animals.

  5. Short-Term Synaptic Plasticity Regulation in Solution-Gated Indium-Gallium-Zinc-Oxide Electric-Double-Layer Transistors.

    PubMed

    Wan, Chang Jin; Liu, Yang Hui; Zhu, Li Qiang; Feng, Ping; Shi, Yi; Wan, Qing

    2016-04-20

    In the biological nervous system, synaptic plasticity regulation is based on the modulation of ionic fluxes, and such regulation was regarded as the fundamental mechanism underlying memory and learning. Inspired by such biological strategies, indium-gallium-zinc-oxide (IGZO) electric-double-layer (EDL) transistors gated by aqueous solutions were proposed for synaptic behavior emulations. Short-term synaptic plasticity, such as paired-pulse facilitation, high-pass filtering, and orientation tuning, was experimentally emulated in these EDL transistors. Most importantly, we found that such short-term synaptic plasticity can be effectively regulated by alcohol (ethyl alcohol) and salt (potassium chloride) additives. Our results suggest that solution gated oxide-based EDL transistors could act as the platforms for short-term synaptic plasticity emulation. PMID:27007748

  6. Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia

    PubMed Central

    Crabtree, Gregg W.; Gogos, Joseph A.

    2014-01-01

    Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID:25505409

  7. Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

    PubMed

    Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

    2015-11-01

    The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus. PMID:25808129

  8. Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

    PubMed

    Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

    2015-11-01

    The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus.

  9. Short-Term Synaptic Plasticity in the Dentate Gyrus of Monkeys

    PubMed Central

    Tamura, Ryoi; Nishida, Hiroshi; Eifuku, Satoshi; Nagao, Kaoru; Fushiki, Hiroaki; Watanabe, Yukio; Ono, Taketoshi

    2011-01-01

    The hippocampus plays an important role in learning and memory. Synaptic plasticity in the hippocampus, short-term and long-term, is postulated to be a neural substrate of memory trace. Paired-pulse stimulation is a standard technique for evaluating a form of short-term synaptic plasticity in rodents. However, evidence is lacking for paired-pulse responses in the primate hippocampus. In the present study, we recorded paired-pulse responses in the dentate gyrus of monkeys while stimulating to the medial part of the perforant path at several inter-pulse intervals (IPIs) using low and high stimulus intensities. When the stimulus intensity was low, the first pulse produced early strong depression (at IPIs of 10–30 ms) and late slight depression (at IPIs of 100–1000 ms) of field excitatory postsynaptic potentials (fEPSPs) generated by the second pulse, interposing no depression IPIs (50–70 ms). When the stimulus intensity was high, fEPSPs generated by the second pulse were depressed by the first pulse at all IPIs except for the longest one (2000 ms). Population spikes (PSs) generated by the second pulse were completely blocked or strongly depressed at shorter IPIs (10–100 or 200 ms, respectively), while no depression or slight facilitation occurred at longer IPIs (500–2000 ms). Administration of diazepam slightly increased fEPSPs, while it decreased PSs produced by the first pulse. It also enhanced the facilitation of PSs produced by the second stimulation at longer IPIs. The present results, in comparison with previous studies using rodents, indicate that paired-pulse responses of fEPSPs in the monkey are basically similar to those of rodents, although paired-pulse responses of PSs in the monkey are more delayed than those in rodents and have a different sensitivity to diazepam. PMID:21625444

  10. Calmodulin as a major calcium buffer shaping vesicular release and short-term synaptic plasticity: facilitation through buffer dislocation.

    PubMed

    Timofeeva, Yulia; Volynski, Kirill E

    2015-01-01

    Action potential-dependent release of synaptic vesicles and short-term synaptic plasticity are dynamically regulated by the endogenous Ca(2+) buffers that shape [Ca(2+)] profiles within a presynaptic bouton. Calmodulin is one of the most abundant presynaptic proteins and it binds Ca(2+) faster than any other characterized endogenous neuronal Ca(2+) buffer. Direct effects of calmodulin on fast presynaptic Ca(2+) dynamics and vesicular release however have not been studied in detail. Using experimentally constrained three-dimensional diffusion modeling of Ca(2+) influx-exocytosis coupling at small excitatory synapses we show that, at physiologically relevant concentrations, Ca(2+) buffering by calmodulin plays a dominant role in inhibiting vesicular release and in modulating short-term synaptic plasticity. We also propose a novel and potentially powerful mechanism for short-term facilitation based on Ca(2+)-dependent dynamic dislocation of calmodulin molecules from the plasma membrane within the active zone. PMID:26190970

  11. Spatiotemporal discrimination in neural networks with short-term synaptic plasticity

    NASA Astrophysics Data System (ADS)

    Shlaer, Benjamin; Miller, Paul

    2015-03-01

    Cells in recurrently connected neural networks exhibit bistability, which allows for stimulus information to persist in a circuit even after stimulus offset, i.e. short-term memory. However, such a system does not have enough hysteresis to encode temporal information about the stimuli. The biophysically described phenomenon of synaptic depression decreases synaptic transmission strengths due to increased presynaptic activity. This short-term reduction in synaptic strengths can destabilize attractor states in excitatory recurrent neural networks, causing the network to move along stimulus dependent dynamical trajectories. Such a network can successfully separate amplitudes and durations of stimuli from the number of successive stimuli. Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression. Front. Comput. Neurosci. 7:59., and so provides a strong candidate network for the encoding of spatiotemporal information. Here we explicitly demonstrate the capability of a recurrent neural network with short-term synaptic depression to discriminate between the temporal sequences in which spatial stimuli are presented.

  12. Astroglial potassium clearance contributes to short-term plasticity of synaptically evoked currents at the tripartite synapse

    PubMed Central

    Sibille, Jérémie; Pannasch, Ulrike; Rouach, Nathalie

    2014-01-01

    Abstract Astroglial processes enclose ∼60% of CA1 hippocampal synapses to form the tripartite synapse. Although astrocytes express ionic channels, neurotransmitter receptors and transporters to detect neuronal activity, the nature, plasticity and impact of the currents induced by neuronal activity on short-term synaptic plasticity remain elusive in hippocampal astrocytes. Using simultaneous electrophysiological recordings of astrocytes and neurons, we found that single stimulation of Schaffer collaterals in hippocampal slices evokes in stratum radiatum astrocytes a complex prolonged inward current synchronized to synaptic and spiking activity in CA1 pyramidal cells. The astroglial current is composed of three components sensitive to neuronal activity, i.e. a long-lasting potassium current mediated by Kir4.1 channels, a transient glutamate transporter current and a slow residual current, partially mediated by GABA transporters and Kir4.1-independent potassium channels. We show that all astroglial membrane currents exhibit activity-dependent short-term plasticity. However, only the astroglial glutamate transporter current displays neuronal-like dynamics and plasticity. As Kir4.1 channel-mediated potassium uptake contributes to 80% of the synaptically evoked astroglial current, we investigated in turn its impact on short-term synaptic plasticity. Using glial conditional Kir4.1 knockout mice, we found that astroglial potassium uptake reduces synaptic responses to repetitive stimulation and post-tetanic potentiation. These results show that astrocytes integrate synaptic activity via multiple ionic channels and transporters and contribute to short-term plasticity in part via potassium clearance mediated by Kir4.1 channels. PMID:24081156

  13. Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses

    PubMed Central

    Katz, Eleonora; Elgoyhen, Ana Belén

    2014-01-01

    The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the α9α10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern. PMID:25520631

  14. Short-term synaptic plasticity can enhance weak signal detectability in nonrenewal spike trains.

    PubMed

    Lüdtke, Niklas; Nelson, Mark E

    2006-12-01

    We study the encoding of weak signals in spike trains with interspike interval (ISI) correlations and the signals' subsequent detection in sensory neurons. Motivated by the observation of negative ISI correlations in auditory and electrosensory afferents, we assess the theoretical performance limits of an individual detector neuron receiving a weak signal distributed across multiple afferent inputs. We assess the functional role of ISI correlations in the detection process using statistical detection theory and derive two sequential likelihood ratio detector models: one for afferents with renewal statistics; the other for afferents with negatively correlated ISIs. We suggest a mechanism that might enable sensory neurons to implicitly compute conditional probabilities of presynaptic spikes by means of short-term synaptic plasticity. We demonstrate how this mechanism can enhance a postsynaptic neuron's sensitivity to weak signals by exploiting the correlation structure of the input spike trains. Our model not only captures fundamental aspects of early electrosensory signal processing in weakly electric fish, but may also bear relevance to the mammalian auditory system and other sensory modalities.

  15. A catalytic independent function of the deubiquitinating enzyme USP14 regulates hippocampal synaptic short-term plasticity and vesicle number

    PubMed Central

    Walters, Brandon J; Hallengren, Jada J; Theile, Christopher S; Ploegh, Hidde L; Wilson, Scott M; Dobrunz, Lynn E

    2014-01-01

    AbstractThe ubiquitin proteasome system is required for the rapid and precise control of protein abundance that is essential for synaptic function. USP14 is a proteasome-bound deubiquitinating enzyme that recycles ubiquitin and regulates synaptic short-term synaptic plasticity. We previously reported that loss of USP14 in axJ mice causes a deficit in paired pulse facilitation (PPF) at hippocampal synapses. Here we report that USP14 regulates synaptic function through a novel, deubiquitination-independent mechanism. Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability. Instead, the loss of USP14 causes a large reduction in the number of synaptic vesicles. Over-expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination. Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment. Overall, we demonstrate a novel, deubiquitination-independent function for USP14 in influencing synaptic architecture and plasticity. PMID:24218545

  16. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    PubMed

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

  17. Short-term synaptic plasticity in the deterministic Tsodyks–Markram model leads to unpredictable network dynamics

    PubMed Central

    Cortes, Jesus M.; Desroches, Mathieu; Rodrigues, Serafim; Veltz, Romain; Muñoz, Miguel A.; Sejnowski, Terrence J.

    2013-01-01

    Short-term synaptic plasticity strongly affects the neural dynamics of cortical networks. The Tsodyks and Markram (TM) model for short-term synaptic plasticity accurately accounts for a wide range of physiological responses at different types of cortical synapses. Here, we report a route to chaotic behavior via a Shilnikov homoclinic bifurcation that dynamically organizes some of the responses in the TM model. In particular, the presence of such a homoclinic bifurcation strongly affects the shape of the trajectories in the phase space and induces highly irregular transient dynamics; indeed, in the vicinity of the Shilnikov homoclinic bifurcation, the number of population spikes and their precise timing are unpredictable and highly sensitive to the initial conditions. Such an irregular deterministic dynamics has its counterpart in stochastic/network versions of the TM model: The existence of the Shilnikov homoclinic bifurcation generates complex and irregular spiking patterns and—acting as a sort of springboard—facilitates transitions between the down-state and unstable periodic orbits. The interplay between the (deterministic) homoclinic bifurcation and stochastic effects may give rise to some of the complex dynamics observed in neural systems. PMID:24062464

  18. Long-term plasticity determines the postsynaptic response to correlated afferents with multivesicular short-term synaptic depression

    PubMed Central

    Bird, Alex D.; Richardson, Magnus J. E.

    2014-01-01

    Synchrony in a presynaptic population leads to correlations in vesicle occupancy at the active sites for neurotransmitter release. The number of independent release sites per presynaptic neuron, a synaptic parameter recently shown to be modified during long-term plasticity, will modulate these correlations and therefore have a significant effect on the firing rate of the postsynaptic neuron. To understand how correlations from synaptic dynamics and from presynaptic synchrony shape the postsynaptic response, we study a model of multiple release site short-term plasticity and derive exact results for the crosscorrelation function of vesicle occupancy and neurotransmitter release, as well as the postsynaptic voltage variance. Using approximate forms for the postsynaptic firing rate in the limits of low and high correlations, we demonstrate that short-term depression leads to a maximum response for an intermediate number of presynaptic release sites, and that this leads to a tuning-curve response peaked at an optimal presynaptic synchrony set by the number of neurotransmitter release sites per presynaptic neuron. These effects arise because, above a certain level of correlation, activity in the presynaptic population is overly strong resulting in wastage of the pool of releasable neurotransmitter. As the nervous system operates under constraints of efficient metabolism it is likely that this phenomenon provides an activity-dependent constraint on network architecture. PMID:24523691

  19. Stability and bifurcation of the Tsodyks-Markram model about short-term synaptic plasticity with time delay

    NASA Astrophysics Data System (ADS)

    Wang, Qiubao

    2014-06-01

    Short-term synaptic plasticity in the Tsodyks-Markram model can lead to unpredictable and complicated network dynamics. In this paper, we present a new Tsodyks-Markram model with time delay as a parameter. The time delay plays a very important role for the dynamics of our model. We report on the existence of Hopf bifurcation in the model for fixed and varied release probability of available neurotransmitters. It is found that there are stability switches, and a supercritical or subcritical Hopf bifurcation occur when the delay passes through a sequence of critical values. We provide numerical results to illustrate our conclusion about stability and obtain the properties of Hopf bifurcation. Moreover, we find the large sensitivity to initial conditions in our model.

  20. Closed-loop Robots Driven by Short-Term Synaptic Plasticity: Emergent Explorative vs. Limit-Cycle Locomotion

    PubMed Central

    Martin, Laura; Sándor, Bulcsú; Gros, Claudius

    2016-01-01

    We examine the hypothesis, that short-term synaptic plasticity (STSP) may generate self-organized motor patterns. We simulated sphere-shaped autonomous robots, within the LPZRobots simulation package, containing three weights moving along orthogonal internal rods. The position of a weight is controlled by a single neuron receiving excitatory input from the sensor, measuring its actual position, and inhibitory inputs from the other two neurons. The inhibitory connections are transiently plastic, following physiologically inspired STSP-rules. We find that a wide palette of motion patterns are generated through the interaction of STSP, robot, and environment (closed-loop configuration), including various forward meandering and circular motions, together with chaotic trajectories. The observed locomotion is robust with respect to additional interactions with obstacles. In the chaotic phase the robot is seemingly engaged in actively exploring its environment. We believe that our results constitute a concept of proof that transient synaptic plasticity, as described by STSP, may potentially be important for the generation of motor commands and for the emergence of complex locomotion patterns, adapting seamlessly also to unexpected environmental feedback. We observe spontaneous and collision induced mode switchings, finding in addition, that locomotion may follow transiently limit cycles which are otherwise unstable. Regular locomotion corresponds to stable limit cycles in the sensorimotor loop, which may be characterized in turn by arbitrary angles of propagation. This degeneracy is, in our analysis, one of the drivings for the chaotic wandering observed for selected parameter settings, which is induced by the smooth diffusion of the angle of propagation. PMID:27803661

  1. Adaptation of short-term plasticity parameters via error-driven learning may explain the correlation between activity-dependent synaptic properties, connectivity motifs and target specificity

    PubMed Central

    Esposito, Umberto; Giugliano, Michele; Vasilaki, Eleni

    2015-01-01

    The anatomical connectivity among neurons has been experimentally found to be largely non-random across brain areas. This means that certain connectivity motifs occur at a higher frequency than would be expected by chance. Of particular interest, short-term synaptic plasticity properties were found to colocalize with specific motifs: an over-expression of bidirectional motifs has been found in neuronal pairs where short-term facilitation dominates synaptic transmission among the neurons, whereas an over-expression of unidirectional motifs has been observed in neuronal pairs where short-term depression dominates. In previous work we found that, given a network with fixed short-term properties, the interaction between short- and long-term plasticity of synaptic transmission is sufficient for the emergence of specific motifs. Here, we introduce an error-driven learning mechanism for short-term plasticity that may explain how such observed correspondences develop from randomly initialized dynamic synapses. By allowing synapses to change their properties, neurons are able to adapt their own activity depending on an error signal. This results in more rich dynamics and also, provided that the learning mechanism is target-specific, leads to specialized groups of synapses projecting onto functionally different targets, qualitatively replicating the experimental results of Wang and collaborators. PMID:25688203

  2. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.

    PubMed

    Nanou, Evanthia; Sullivan, Jane M; Scheuer, Todd; Catterall, William A

    2016-01-26

    Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.

  3. A model of order-selectivity based on dynamic changes in the balance of excitation and inhibition produced by short-term synaptic plasticity

    PubMed Central

    Goudar, Vishwa

    2014-01-01

    Determining the order of sensory events separated by a few hundred milliseconds is critical to many forms of sensory processing, including vocalization and speech discrimination. Although many experimental studies have recorded from auditory order-sensitive and order-selective neurons, the underlying mechanisms are poorly understood. Here we demonstrate that universal properties of cortical synapses—short-term synaptic plasticity of excitatory and inhibitory synapses—are well suited for the generation of order-selective neural responses. Using computational models of canonical disynaptic circuits, we show that the dynamic changes in the balance of excitation and inhibition imposed by short-term plasticity lead to the generation of order-selective responses. Parametric analyses predict that among the forms of short-term plasticity expressed at excitatory-to-excitatory, excitatory-to-inhibitory, and inhibitory-to-excitatory synapses, the single most important contributor to order-selectivity is the paired-pulse depression of inhibitory postsynaptic potentials (IPSPs). A topographic model of the auditory cortex that incorporates short-term plasticity accounts for both context-dependent suppression and enhancement in response to paired tones. Together these results provide a framework to account for an important computational problem based on ubiquitous synaptic properties that did not yet have a clearly established computational function. Additionally, these studies suggest that disynaptic circuits represent a fundamental computational unit that is capable of processing both spatial and temporal information. PMID:25339707

  4. Simulation of synaptic short-term plasticity using Ba(CF3SO3)2-doped polyethylene oxide electrolyte film

    NASA Astrophysics Data System (ADS)

    Chang, C. T.; Zeng, F.; Li, X. J.; Dong, W. S.; Lu, S. H.; Gao, S.; Pan, F.

    2016-01-01

    The simulation of synaptic plasticity using new materials is critical in the study of brain-inspired computing. Devices composed of Ba(CF3SO3)2-doped polyethylene oxide (PEO) electrolyte film were fabricated and with pulse responses found to resemble the synaptic short-term plasticity (STP) of both short-term depression (STD) and short-term facilitation (STF) synapses. The values of the charge and discharge peaks of the pulse responses did not vary with input number when the pulse frequency was sufficiently low(~1 Hz). However, when the frequency was increased, the charge and discharge peaks decreased and increased, respectively, in gradual trends and approached stable values with respect to the input number. These stable values varied with the input frequency, which resulted in the depressed and potentiated weight modifications of the charge and discharge peaks, respectively. These electrical properties simulated the high and low band-pass filtering effects of STD and STF, respectively. The simulations were consistent with biological results and the corresponding biological parameters were successfully extracted. The study verified the feasibility of using organic electrolytes to mimic STP.

  5. Simulation of synaptic short-term plasticity using Ba(CF3SO3)2-doped polyethylene oxide electrolyte film

    PubMed Central

    Chang, C. T.; Zeng, F.; Li, X. J.; Dong, W. S.; Lu, S. H.; Gao, S.; Pan, F.

    2016-01-01

    The simulation of synaptic plasticity using new materials is critical in the study of brain-inspired computing. Devices composed of Ba(CF3SO3)2-doped polyethylene oxide (PEO) electrolyte film were fabricated and with pulse responses found to resemble the synaptic short-term plasticity (STP) of both short-term depression (STD) and short-term facilitation (STF) synapses. The values of the charge and discharge peaks of the pulse responses did not vary with input number when the pulse frequency was sufficiently low(~1 Hz). However, when the frequency was increased, the charge and discharge peaks decreased and increased, respectively, in gradual trends and approached stable values with respect to the input number. These stable values varied with the input frequency, which resulted in the depressed and potentiated weight modifications of the charge and discharge peaks, respectively. These electrical properties simulated the high and low band-pass filtering effects of STD and STF, respectively. The simulations were consistent with biological results and the corresponding biological parameters were successfully extracted. The study verified the feasibility of using organic electrolytes to mimic STP. PMID:26739613

  6. Effects of treadmill running on short-term pre-synaptic plasticity at dentate gyrus of streptozotocin-induced diabetic rats.

    PubMed

    Reisi, Parham; Babri, Shirin; Alaei, Hojjatallah; Sharifi, Mohammad Reza; Mohaddes, Gisue; Lashgari, Reza

    2008-05-23

    Previous studies indicated that diabetes mellitus leads to impairments in hippocampal synaptic plasticity and defects in learning and memory. Although diabetes affects synaptic transmission in the hippocampus through both pre- and post-synaptic influences, it is not clear if the defects are pre- or post-synaptic or both; and whether these are prevented by running. The aim of this study was to evaluate the effects of treadmill running on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups were the control-rest group, the control-exercise group, the diabetes-rest group and the diabetes-exercise group (n=6 for each experimental group). The exercise program was moderate exercise consisting of treadmill running at 17 m/min and 0-degree inclination for 40 min/day, 7 days/week, for 12 weeks. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In the diabetic-rest group paired pulse facilitation was significantly increased comparing to the control-rest group. However, there were no differences between responses of the control-exercise and diabetes-exercise groups compared to the control-rest group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that treadmill running prevents this effect. The data support the possibility that alterations in transmission may account, in part, for learning and memory deficits induced in diabetes, and that treadmill running is helpful in alleviating the neural complications of diabetes mellitus.

  7. Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels.

    PubMed

    Nanou, Evanthia; Yan, Jin; Whitehead, Nicholas P; Kim, Min Jeong; Froehner, Stanley C; Scheuer, Todd; Catterall, William A

    2016-01-26

    Facilitation and inactivation of P/Q-type calcium (Ca(2+)) currents through the regulation of voltage-gated Ca(2+) (CaV) 2.1 channels by Ca(2+) sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca(2+) entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.

  8. Effect of short-term exposure to dichlorvos on synaptic plasticity of rat hippocampal slices: Involvement of acylpeptide hydrolase and {alpha}{sub 7} nicotinic receptors

    SciTech Connect

    Olmos, Cristina; Sandoval, Rodrigo; Rozas, Carlos; Navarro, Sebastian; Wyneken, Ursula; Zeise, Marc; Morales, Bernardo; Pancetti, Floria

    2009-07-01

    Dichlorvos is the active molecule of the pro-drug metrifonate used to revert the cognitive deficits associated with Alzheimer's disease. A few years ago it was reported that dichlorvos inhibits the enzyme acylpeptide hydrolase at lower doses than those necessary to inhibit acetylcholinesterase to the same extent. Therefore, the aim of our investigation was to test the hypothesis that dichlorvos can enhance synaptic efficacy through a mechanism that involves acylpeptide hydrolase instead of acetylcholinesterase inhibition. We used long-term potentiation induced in rat hippocampal slices as a model of synaptic plasticity. Our results indicate that short-term exposures (20 min) to 50 {mu}M dichlorvos enhance long-term potentiation in about 200% compared to the control condition. This effect is correlated with approximately 60% inhibition of acylpeptide hydrolase activity, whereas acetylcholinesterase activity remains unaffected. Paired-pulse facilitation and inhibition experiments indicate that dichlorvos does not have any presynaptic effect in the CA3 {yields} CA1 pathway nor affect gabaergic interneurons. Interestingly, the application of 100 nM methyllicaconitine, an {alpha}{sub 7} nicotinic receptor antagonist, blocked the enhancing effect of dichlorvos on long-term potentiation. These results indicate that under the exposure conditions described above, dichlorvos enhances long-term potentiation through a postsynaptic mechanism that involves (a) the inhibition of the enzyme acylpeptide hydrolase and (b) the modulation of {alpha}{sub 7} nicotinic receptors.

  9. Joining distributed pattern processing and homeostatic plasticity in recurrent on-center off-surround shunting networks: noise, saturation, short-term memory, synaptic scaling, and BDNF.

    PubMed

    Chandler, Ben; Grossberg, Stephen

    2012-01-01

    The activities of neurons vary within small intervals that are bounded both above and below, yet the inputs to these neurons may vary many-fold. How do networks of neurons process distributed input patterns effectively under these conditions? If a large number of input sources intermittently converge on a cell through time, then a serious design problem arises: if cell activities are sensitive to large inputs, then why do not small inputs get lost in internal system noise? If cell activities are sensitive to small inputs, then why do they not all saturate at their maximum values in response to large inputs and thereby become incapable of processing analog differences in inputs across an entire network? Grossberg (1973) solved this noise-saturation dilemma using neurons that obey the membrane, or shunting, equations of neurophysiology interacting in recurrent and non-recurrent on-center off-surround networks, and showed how different signal functions can influence the activity patterns that the network stores in short-term memory. These results demonstrated that maintaining a balance between excitation and inhibition in a neural network is essential to process distributed patterns of inputs and signals without experiencing the catastrophies of noise or saturation. However, shunting on-center off-surround networks only guarantee that cell activities remain sensitive to the relative sizes of inputs and recurrent signals, but not that they will use the full dynamic range that each cell can support. Additional homeostatic plasticity mechanisms are needed to anchor the activities of networks to exploit their full dynamic range. This article shows how mechanisms of synaptic scaling can be incorporated within recurrent on-center off-surround networks in such a way that their pattern processing capabilities, including the ability to make winner-take-all decisions, is preserved. This model generalizes the synaptic scaling model of van Rossum, Bi, & Turrigiano (2000) for a

  10. Emulating short-term synaptic dynamics with memristive devices

    PubMed Central

    Berdan, Radu; Vasilaki, Eleni; Khiat, Ali; Indiveri, Giacomo; Serb, Alexandru; Prodromakis, Themistoklis

    2016-01-01

    Neuromorphic architectures offer great promise for achieving computation capacities beyond conventional Von Neumann machines. The essential elements for achieving this vision are highly scalable synaptic mimics that do not undermine biological fidelity. Here we demonstrate that single solid-state TiO2 memristors can exhibit non-associative plasticity phenomena observed in biological synapses, supported by their metastable memory state transition properties. We show that, contrary to conventional uses of solid-state memory, the existence of rate-limiting volatility is a key feature for capturing short-term synaptic dynamics. We also show how the temporal dynamics of our prototypes can be exploited to implement spatio-temporal computation, demonstrating the memristors full potential for building biophysically realistic neural processing systems. PMID:26725838

  11. Low level postnatal methylmercury exposure in vivo alters developmental forms of short-term synaptic plasticity in the visual cortex of rat

    SciTech Connect

    Dasari, Sameera; Yuan, Yukun

    2009-11-01

    Methylmercury (MeHg) has been previously shown to affect neurotransmitter release. Short-term synaptic plasticity (STP) is primarily related to changes in the probability of neurotransmitter release. To determine if MeHg affects STP development, we examined STP forms in the visual cortex of rat following in vivo MeHg exposure. Neonatal rats received 0 (0.9% NaCl), 0.75 or 1.5 mg/kg/day MeHg subcutaneously for 15 or 30 days beginning on postnatal day 5, after which visual cortical slices were prepared for field potential recordings. In slices prepared from rats treated with vehicle, field excitatory postsynaptic potentials (fEPSPs) evoked by paired-pulse stimulation at 20-200 ms inter-stimulus intervals showed a depression (PPD) of the second fEPSP (fEPSP2). PPD was also seen in slices prepared from rats after 15 day treatment with 0.75 or 1.5 mg/kg/day MeHg. However, longer duration treatment (30 days) with either dose of MeHg resulted in paired-pulse facilitation (PPF) of fEPSP2 in the majority of slices examined. PPF remained observable in slices prepared from animals in which MeHg exposure had been terminated for 30 days after completion of the initial 30 day MeHg treatment, whereas slices from control animals still showed PPD. MeHg did not cause any frequency- or region-preferential effect on STP. Manipulations of [Ca{sup 2+}]{sub e} or application of the GABA{sub A} receptor antagonist bicuculline could alter the strength and polarity of MeHg-induced changes in STP. Thus, these data suggest that low level postnatal MeHg exposure interferes with the developmental transformation of STP in the visual cortex, which is a long-lasting effect.

  12. Robust short-term memory without synaptic learning.

    PubMed

    Johnson, Samuel; Marro, J; Torres, Joaquín J

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings. PMID:23349664

  13. Robust Short-Term Memory without Synaptic Learning

    PubMed Central

    Johnson, Samuel; Marro, J.; Torres, Joaquín J.

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can – as a gradual modification of synaptic weights – since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings. PMID:23349664

  14. Diverse thalamocortical short-term plasticity elicited by ongoing stimulation.

    PubMed

    Díaz-Quesada, Marta; Martini, Francisco J; Ferrati, Giovanni; Bureau, Ingrid; Maravall, Miguel

    2014-01-01

    To produce sensation, neuronal pathways must transmit and process stimulus patterns that unfold over time. This behavior is determined by short-term synaptic plasticity (STP), which shapes the temporal filtering properties of synapses in a pathway. We explored STP variability across thalamocortical (TC) synapses, measuring whole-cell responses to stimulation of TC fibers in layer 4 neurons of mouse barrel cortex in vitro. As expected, STP during stimulation from rest was dominated by depression. However, STP during ongoing stimulation was strikingly diverse across TC connections. Diversity took the form of variable tuning to the latest interstimulus interval: some connections responded weakly to shorter intervals, while other connections were facilitated. These behaviors did not cluster into categories but formed a continuum. Diverse tuning did not require disynaptic inhibition. Hence, monosynaptic excitatory lemniscal TC connections onto layer 4 do not behave uniformly during ongoing stimulation. Each connection responds differentially to particular stimulation intervals, enriching the ability of the pathway to convey complex, temporally fluctuating information.

  15. Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway

    PubMed Central

    Simons-Weidenmaier, Nadine S; Weber, Maruschka; Plappert, Claudia F; Pilz, Peter KD; Schmid, Susanne

    2006-01-01

    Background Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons. Results Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically. Conclusion Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the Pn

  16. Synchronization stability and firing transitions in two types of class I neuronal networks with short-term plasticity.

    PubMed

    Zhang, Honghui; Wang, Qingyun; He, Xiaoyan; Chen, Guanrong

    2014-01-01

    This paper investigates synchronization stability and firing transition in two types of the modified canonical class I neuronal networks, where the short-term plasticity of synapse is introduced. We mainly consider both unidirectional chain and global coupling configurations. Previous studies have shown that the coupled class I neurons can spontaneously de-synchronize. Presently, the short-term plasticity of synapse is considered to check the universality of this phenomenon. Based on the theoretical analysis and numerical simulation, it is shown that unidirectionally chain coupled class I neurons can realize synchronization, whereas bidirectionally coupled chain neurons cannot synchronize, and globally coupled class I neurons de-synchronize. Furthermore, the dynamics of coupled neurons with different firing modes are also studied in numerical simulations, and interesting transitions of different firing modes can be induced by the short-term plasticity. The obtained results can be helpful to further understand important effects of the short-term synaptic plasticity on realistic neuronal systems.

  17. Short-Term Plasticity and Long-Term Potentiation in Magnetic Tunnel Junctions: Towards Volatile Synapses

    NASA Astrophysics Data System (ADS)

    Sengupta, Abhronil; Roy, Kaushik

    2016-02-01

    Synaptic memory is considered to be the main element responsible for learning and cognition in humans. Although traditionally nonvolatile long-term plasticity changes are implemented in nanoelectronic synapses for neuromorphic applications, recent studies in neuroscience reveal that biological synapses undergo metastable volatile strengthening followed by a long-term strengthening provided that the frequency of the input stimulus is sufficiently high. Such "memory strengthening" and "memory decay" functionalities can potentially lead to adaptive neuromorphic architectures. In this paper, we demonstrate the close resemblance of the magnetization dynamics of a magnetic tunnel junction (MTJ) to short-term plasticity and long-term potentiation observed in biological synapses. We illustrate that, in addition to the magnitude and duration of the input stimulus, the frequency of the stimulus plays a critical role in determining long-term potentiation of the MTJ. Such MTJ synaptic memory arrays can be utilized to create compact, ultrafast, and low-power intelligent neural systems.

  18. Short-term plasticity in thalamocortical pathways: cellular mechanisms and functional roles.

    PubMed

    Castro-Alamancos, M A

    1997-01-01

    Information reaches the neocortex through different types of thalamocortical pathways. These differ in many morphological and physiological properties. One interesting aspect in which thalamocortical pathways differ is in their temporal dynamics, such as their short-term plasticity. Primary pathways display frequency-dependent depression, while secondary pathways display frequency-dependent enhancement. The cellular mechanisms underlying these dynamic responses involve pre- and post-synaptic and circuit properties. They may serve to synchronize, amplify and/or filter neural activity in neocortex depending on behavioral demands, and thus to adapt each pathway to its specific function.

  19. Target-cell-specific short-term plasticity in local circuits.

    PubMed

    Blackman, Arne V; Abrahamsson, Therese; Costa, Rui Ponte; Lalanne, Txomin; Sjöström, P Jesper

    2013-01-01

    Short-term plasticity (STP) denotes changes in synaptic strength that last up to tens of seconds. It is generally thought that STP impacts information transfer across synaptic connections and may thereby provide neurons with, for example, the ability to detect input coherence, to maintain stability and to promote synchronization. STP is due to a combination of mechanisms, including vesicle depletion and calcium accumulation in synaptic terminals. Different forms of STP exist, depending on many factors, including synapse type. Recent evidence shows that synapse dependence holds true even for connections that originate from a single presynaptic cell, which implies that postsynaptic target cell type can determine synaptic short-term dynamics. This arrangement is surprising, since STP itself is chiefly due to presynaptic mechanisms. Target-specific synaptic dynamics in addition imply that STP is not a bug resulting from synapses fatiguing when driven too hard, but rather a feature that is selectively implemented in the brain for specific functional purposes. As an example, target-specific STP results in sequential somatic and dendritic inhibition in neocortical and hippocampal excitatory cells during high-frequency firing. Recent studies also show that the Elfn1 gene specifically controls STP at some synapse types. In addition, presynaptic NMDA receptors have been implicated in synapse-specific control of synaptic dynamics during high-frequency activity. We argue that synapse-specific STP deserves considerable further study, both experimentally and theoretically, since its function is not well known. We propose that synapse-specific STP has to be understood in the context of the local circuit, which requires combining different scientific disciplines ranging from molecular biology through electrophysiology to computer modeling. PMID:24367330

  20. Target-cell-specific short-term plasticity in local circuits

    PubMed Central

    Blackman, Arne V.; Abrahamsson, Therese; Costa, Rui Ponte; Lalanne, Txomin; Sjöström, P. Jesper

    2013-01-01

    Short-term plasticity (STP) denotes changes in synaptic strength that last up to tens of seconds. It is generally thought that STP impacts information transfer across synaptic connections and may thereby provide neurons with, for example, the ability to detect input coherence, to maintain stability and to promote synchronization. STP is due to a combination of mechanisms, including vesicle depletion and calcium accumulation in synaptic terminals. Different forms of STP exist, depending on many factors, including synapse type. Recent evidence shows that synapse dependence holds true even for connections that originate from a single presynaptic cell, which implies that postsynaptic target cell type can determine synaptic short-term dynamics. This arrangement is surprising, since STP itself is chiefly due to presynaptic mechanisms. Target-specific synaptic dynamics in addition imply that STP is not a bug resulting from synapses fatiguing when driven too hard, but rather a feature that is selectively implemented in the brain for specific functional purposes. As an example, target-specific STP results in sequential somatic and dendritic inhibition in neocortical and hippocampal excitatory cells during high-frequency firing. Recent studies also show that the Elfn1 gene specifically controls STP at some synapse types. In addition, presynaptic NMDA receptors have been implicated in synapse-specific control of synaptic dynamics during high-frequency activity. We argue that synapse-specific STP deserves considerable further study, both experimentally and theoretically, since its function is not well known. We propose that synapse-specific STP has to be understood in the context of the local circuit, which requires combining different scientific disciplines ranging from molecular biology through electrophysiology to computer modeling. PMID:24367330

  1. Behavior control in the sensorimotor loop with short-term synaptic dynamics induced by self-regulating neurons.

    PubMed

    Toutounji, Hazem; Pasemann, Frank

    2014-01-01

    The behavior and skills of living systems depend on the distributed control provided by specialized and highly recurrent neural networks. Learning and memory in these systems is mediated by a set of adaptation mechanisms, known collectively as neuronal plasticity. Translating principles of recurrent neural control and plasticity to artificial agents has seen major strides, but is usually hampered by the complex interactions between the agent's body and its environment. One of the important standing issues is for the agent to support multiple stable states of behavior, so that its behavioral repertoire matches the requirements imposed by these interactions. The agent also must have the capacity to switch between these states in time scales that are comparable to those by which sensory stimulation varies. Achieving this requires a mechanism of short-term memory that allows the neurocontroller to keep track of the recent history of its input, which finds its biological counterpart in short-term synaptic plasticity. This issue is approached here by deriving synaptic dynamics in recurrent neural networks. Neurons are introduced as self-regulating units with a rich repertoire of dynamics. They exhibit homeostatic properties for certain parameter domains, which result in a set of stable states and the required short-term memory. They can also operate as oscillators, which allow them to surpass the level of activity imposed by their homeostatic operation conditions. Neural systems endowed with the derived synaptic dynamics can be utilized for the neural behavior control of autonomous mobile agents. The resulting behavior depends also on the underlying network structure, which is either engineered or developed by evolutionary techniques. The effectiveness of these self-regulating units is demonstrated by controlling locomotion of a hexapod with 18 degrees of freedom, and obstacle-avoidance of a wheel-driven robot. PMID:24904403

  2. Behavior control in the sensorimotor loop with short-term synaptic dynamics induced by self-regulating neurons

    PubMed Central

    Toutounji, Hazem; Pasemann, Frank

    2014-01-01

    The behavior and skills of living systems depend on the distributed control provided by specialized and highly recurrent neural networks. Learning and memory in these systems is mediated by a set of adaptation mechanisms, known collectively as neuronal plasticity. Translating principles of recurrent neural control and plasticity to artificial agents has seen major strides, but is usually hampered by the complex interactions between the agent's body and its environment. One of the important standing issues is for the agent to support multiple stable states of behavior, so that its behavioral repertoire matches the requirements imposed by these interactions. The agent also must have the capacity to switch between these states in time scales that are comparable to those by which sensory stimulation varies. Achieving this requires a mechanism of short-term memory that allows the neurocontroller to keep track of the recent history of its input, which finds its biological counterpart in short-term synaptic plasticity. This issue is approached here by deriving synaptic dynamics in recurrent neural networks. Neurons are introduced as self-regulating units with a rich repertoire of dynamics. They exhibit homeostatic properties for certain parameter domains, which result in a set of stable states and the required short-term memory. They can also operate as oscillators, which allow them to surpass the level of activity imposed by their homeostatic operation conditions. Neural systems endowed with the derived synaptic dynamics can be utilized for the neural behavior control of autonomous mobile agents. The resulting behavior depends also on the underlying network structure, which is either engineered or developed by evolutionary techniques. The effectiveness of these self-regulating units is demonstrated by controlling locomotion of a hexapod with 18 degrees of freedom, and obstacle-avoidance of a wheel-driven robot. PMID:24904403

  3. Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory

    PubMed Central

    Hausrat, Torben J.; Muhia, Mary; Gerrow, Kimberly; Thomas, Philip; Hirdes, Wiebke; Tsukita, Sachiko; Heisler, Frank F.; Herich, Lena; Dubroqua, Sylvain; Breiden, Petra; Feldon, Joram; Schwarz, Jürgen R; Yee, Benjamin K.; Smart, Trevor G.; Triller, Antoine; Kneussel, Matthias

    2015-01-01

    Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs. PMID:25891999

  4. Short-term plasticity and long-term potentiation mimicked in single inorganic synapses

    NASA Astrophysics Data System (ADS)

    Ohno, Takeo; Hasegawa, Tsuyoshi; Tsuruoka, Tohru; Terabe, Kazuya; Gimzewski, James K.; Aono, Masakazu

    2011-08-01

    Memory is believed to occur in the human brain as a result of two types of synaptic plasticity: short-term plasticity (STP) and long-term potentiation (LTP; refs , , , ). In neuromorphic engineering, emulation of known neural behaviour has proven to be difficult to implement in software because of the highly complex interconnected nature of thought processes. Here we report the discovery of a Ag2S inorganic synapse, which emulates the synaptic functions of both STP and LTP characteristics through the use of input pulse repetition time. The structure known as an atomic switch, operating at critical voltages, stores information as STP with a spontaneous decay of conductance level in response to intermittent input stimuli, whereas frequent stimulation results in a transition to LTP. The Ag2S inorganic synapse has interesting characteristics with analogies to an individual biological synapse, and achieves dynamic memorization in a single device without the need of external preprogramming. A psychological model related to the process of memorizing and forgetting is also demonstrated using the inorganic synapses. Our Ag2S element indicates a breakthrough in mimicking synaptic behaviour essential for the further creation of artificial neural systems that emulate characteristics of human memory.

  5. Reduced SNAP-25 alters short-term plasticity at developing glutamatergic synapses.

    PubMed

    Antonucci, Flavia; Corradini, Irene; Morini, Raffaella; Fossati, Giuliana; Menna, Elisabetta; Pozzi, Davide; Pacioni, Simone; Verderio, Claudia; Bacci, Alberto; Matteoli, Michela

    2013-07-01

    SNAP-25 is a key component of the synaptic-vesicle fusion machinery, involved in several psychiatric diseases including schizophrenia and ADHD. SNAP-25 protein expression is lower in different brain areas of schizophrenic patients and in ADHD mouse models. How the reduced expression of SNAP-25 alters the properties of synaptic transmission, leading to a pathological phenotype, is unknown. We show that, unexpectedly, halved SNAP-25 levels at 13-14 DIV not only fail to impair synaptic transmission but instead enhance evoked glutamatergic neurotransmission. This effect is possibly dependent on presynaptic voltage-gated calcium channel activity and is not accompanied by changes in spontaneous quantal events or in the pool of readily releasable synaptic vesicles. Notably, synapses of 13-14 DIV neurons with reduced SNAP-25 expression show paired-pulse depression as opposed to paired-pulse facilitation occurring in their wild-type counterparts. This phenotype disappears with synapse maturation. As alterations in short-term plasticity represent a new mechanism contributing to cognitive impairments in intellectual disabilities, our data provide mechanistic clues for neuronal circuit alterations in psychiatric diseases characterized by reduced expression of SNAP-25. PMID:23732542

  6. Translational control of synaptic plasticity.

    PubMed

    Richter, Joel D

    2010-12-01

    Synapses, points of contact between axons and dendrites, are conduits for the flow of information in the circuitry of the central nervous system. The strength of synaptic transmission reflects the interconnectedness of the axons and dendrites at synapses; synaptic strength in turn is modified by the frequency with which the synapses are stimulated. This modulation of synaptic strength, or synaptic plasticity, probably forms the cellular basis for learning and memory. RNA metabolism, particularly translational control at or near the synapse, is one process that controls long-lasting synaptic plasticity and, by extension, memory formation and consolidation. In the present paper, I review some salient features of translational control of synaptic plasticity.

  7. Downstream Effect of Ramping Neuronal Activity through Synapses with Short-Term Plasticity.

    PubMed

    Wei, Wei; Wang, Xiao-Jing

    2016-04-01

    Ramping neuronal activity refers to spiking activity with a rate that increases quasi-linearly over time. It has been observed in multiple cortical areas and is correlated with evidence accumulation processes or timing. In this work, we investigated the downstream effect of ramping neuronal activity through synapses that display short-term facilitation (STF) or depression (STD). We obtained an analytical result for a synapse driven by deterministic linear ramping input that exhibits pure STF or STD and numerically investigated the general case when a synapse displays both STF and STD. We show that the analytical deterministic solution gives an accurate description of the averaging synaptic activation of many inputs converging onto a postsynaptic neuron, even when fluctuations in the ramping input are strong. Activation of a synapse with STF shows an initial cubical increase with time, followed by a linear ramping similar to a synapse without STF. Activation of a synapse with STD grows in time to a maximum before falling and reaching a plateau, and this steady state is independent of the slope of the ramping input. For a synapse displaying both STF and STD, an increase in the depression time constant from a value much smaller than the facilitation time constant τ(F) to a value much larger than τ(F) leads to a transition from facilitation dominance to depression dominance. Therefore, our work provides insights into the impact of ramping neuronal activity on downstream neurons through synapses that display short-term plasticity. In a perceptual decision-making process, ramping activity has been observed in the parietal and prefrontal cortices, with a slope that decreases with task difficulty. Our work predicts that neurons downstream from such a decision circuit could instead display a firing plateau independent of the task difficulty, provided that the synaptic connection is endowed with short-term depression. PMID:26890350

  8. Optogenetics and synaptic plasticity.

    PubMed

    Xie, Yu-feng; Jackson, Michael F; Macdonald, John F

    2013-11-01

    The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.

  9. Rich spectrum of neural field dynamics in the presence of short-term synaptic depression.

    PubMed

    Wang, He; Lam, Kin; Fung, C C Alan; Wong, K Y Michael; Wu, Si

    2015-09-01

    In continuous attractor neural networks (CANNs), spatially continuous information such as orientation, head direction, and spatial location is represented by Gaussian-like tuning curves that can be displaced continuously in the space of the preferred stimuli of the neurons. We investigate how short-term synaptic depression (STD) can reshape the intrinsic dynamics of the CANN model and its responses to a single static input. In particular, CANNs with STD can support various complex firing patterns and chaotic behaviors. These chaotic behaviors have the potential to encode various stimuli in the neuronal system. PMID:26465541

  10. Rich spectrum of neural field dynamics in the presence of short-term synaptic depression

    NASA Astrophysics Data System (ADS)

    Wang, He; Lam, Kin; Fung, C. C. Alan; Wong, K. Y. Michael; Wu, Si

    2015-09-01

    In continuous attractor neural networks (CANNs), spatially continuous information such as orientation, head direction, and spatial location is represented by Gaussian-like tuning curves that can be displaced continuously in the space of the preferred stimuli of the neurons. We investigate how short-term synaptic depression (STD) can reshape the intrinsic dynamics of the CANN model and its responses to a single static input. In particular, CANNs with STD can support various complex firing patterns and chaotic behaviors. These chaotic behaviors have the potential to encode various stimuli in the neuronal system.

  11. Mathematical analysis and algorithms for efficiently and accurately implementing stochastic simulations of short-term synaptic depression and facilitation.

    PubMed

    McDonnell, Mark D; Mohan, Ashutosh; Stricker, Christian

    2013-01-01

    The release of neurotransmitter vesicles after arrival of a pre-synaptic action potential (AP) at cortical synapses is known to be a stochastic process, as is the availability of vesicles for release. These processes are known to also depend on the recent history of AP arrivals, and this can be described in terms of time-varying probabilities of vesicle release. Mathematical models of such synaptic dynamics frequently are based only on the mean number of vesicles released by each pre-synaptic AP, since if it is assumed there are sufficiently many vesicle sites, then variance is small. However, it has been shown recently that variance across sites can be significant for neuron and network dynamics, and this suggests the potential importance of studying short-term plasticity using simulations that do generate trial-to-trial variability. Therefore, in this paper we study several well-known conceptual models for stochastic availability and release. We state explicitly the random variables that these models describe and propose efficient algorithms for accurately implementing stochastic simulations of these random variables in software or hardware. Our results are complemented by mathematical analysis and statement of pseudo-code algorithms.

  12. Presynaptic Adenosine Receptor-Mediated Regulation of Diverse Thalamocortical Short-Term Plasticity in the Mouse Whisker Pathway.

    PubMed

    Ferrati, Giovanni; Martini, Francisco J; Maravall, Miguel

    2016-01-01

    Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In "driver" thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release. PMID:26941610

  13. Presynaptic Adenosine Receptor-Mediated Regulation of Diverse Thalamocortical Short-Term Plasticity in the Mouse Whisker Pathway.

    PubMed

    Ferrati, Giovanni; Martini, Francisco J; Maravall, Miguel

    2016-01-01

    Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In "driver" thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release.

  14. Circadian Regulation of Synaptic Plasticity

    PubMed Central

    Frank, Marcos G.

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  15. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  16. Downstream effect of ramping neural activity through synapses with short-term plasticity

    PubMed Central

    Wei, Wei; Wang, Xiao-Jing

    2016-01-01

    Ramping neuronal activity has been observed in multiple cortical areas correlated with evidence accumulation processes or timing. In this work we investigate the downstream effect of ramping neuronal activity through synapses that display short-term facilitation (STF) or depression (STD). We obtain an analytical result for a synapse driven by deterministic linear ramping input that exhibits pure STF or STD, and investigate the general case when both STF and STD exist numerically. In neural circuits, the ramping inputs usually have strong fluctuation and each downstream neuron receives converging inputs from many presynaptic neurons. We show that the analytical deterministic solution gives an accurate description of the averaging synaptic activation that a postsynaptic neuron receives in a neural circuit, even when the fluctuation in ramping input is strong. Therefore our work provides insights on the impact of ramping neuronal activity on downstream neurons through synapses displaying short-term plasticity. Specifically, activation of a synapse with STF shows a sublinear increase with time and is insensitive to the slopes of ramping inputs during the initial period, followed by a linear ramping similar to a synapse without STF. Activation of a synapse with STD, on the other hand, develops a local maximum before reaching a steady state, which is independent of the slope of ramping input. For a synapse displaying both STF and STD, increase of the depression time constant from a value much smaller than the facilitation time constant τF to a value much larger than τF leads to a transition from facilitation domination to depression domination. By utilizing STD in the corticostriatal synapses, our work provides an understanding of the saturation of striatal activity as observed for monkeys performing evidence accumulation. Our work also predicts that in the fixed duration version of motion discrimination tasks the stationary state of neuronal activity downstream to the

  17. Synaptic Plasticity and Translation Initiation

    ERIC Educational Resources Information Center

    Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

    2004-01-01

    It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

  18. Spines slow down dendritic chloride diffusion and affect short-term ionic plasticity of GABAergic inhibition

    NASA Astrophysics Data System (ADS)

    Mohapatra, Namrata; Tønnesen, Jan; Vlachos, Andreas; Kuner, Thomas; Deller, Thomas; Nägerl, U. Valentin; Santamaria, Fidel; Jedlicka, Peter

    2016-03-01

    Cl‑ plays a crucial role in neuronal function and synaptic inhibition. However, the impact of neuronal morphology on the diffusion and redistribution of intracellular Cl‑ is not well understood. The role of spines in Cl‑ diffusion along dendritic trees has not been addressed so far. Because measuring fast and spatially restricted Cl‑ changes within dendrites is not yet technically possible, we used computational approaches to predict the effects of spines on Cl‑ dynamics in morphologically complex dendrites. In all morphologies tested, including dendrites imaged by super-resolution STED microscopy in live brain tissue, spines slowed down longitudinal Cl‑ diffusion along dendrites. This effect was robust and could be observed in both deterministic as well as stochastic simulations. Cl‑ extrusion altered Cl‑ diffusion to a much lesser extent than the presence of spines. The spine-dependent slowing of Cl‑ diffusion affected the amount and spatial spread of changes in the GABA reversal potential thereby altering homosynaptic as well as heterosynaptic short-term ionic plasticity at GABAergic synapses in dendrites. Altogether, our results suggest a fundamental role of dendritic spines in shaping Cl‑ diffusion, which could be of relevance in the context of pathological conditions where spine densities and neural excitability are perturbed.

  19. Spines slow down dendritic chloride diffusion and affect short-term ionic plasticity of GABAergic inhibition

    PubMed Central

    Mohapatra, Namrata; Tønnesen, Jan; Vlachos, Andreas; Kuner, Thomas; Deller, Thomas; Nägerl, U. Valentin; Santamaria, Fidel; Jedlicka, Peter

    2016-01-01

    Cl− plays a crucial role in neuronal function and synaptic inhibition. However, the impact of neuronal morphology on the diffusion and redistribution of intracellular Cl− is not well understood. The role of spines in Cl− diffusion along dendritic trees has not been addressed so far. Because measuring fast and spatially restricted Cl− changes within dendrites is not yet technically possible, we used computational approaches to predict the effects of spines on Cl− dynamics in morphologically complex dendrites. In all morphologies tested, including dendrites imaged by super-resolution STED microscopy in live brain tissue, spines slowed down longitudinal Cl− diffusion along dendrites. This effect was robust and could be observed in both deterministic as well as stochastic simulations. Cl− extrusion altered Cl− diffusion to a much lesser extent than the presence of spines. The spine-dependent slowing of Cl− diffusion affected the amount and spatial spread of changes in the GABA reversal potential thereby altering homosynaptic as well as heterosynaptic short-term ionic plasticity at GABAergic synapses in dendrites. Altogether, our results suggest a fundamental role of dendritic spines in shaping Cl− diffusion, which could be of relevance in the context of pathological conditions where spine densities and neural excitability are perturbed. PMID:26987404

  20. Switched-capacitor realization of presynaptic short-term-plasticity and stop-learning synapses in 28 nm CMOS

    PubMed Central

    Noack, Marko; Partzsch, Johannes; Mayr, Christian G.; Hänzsche, Stefan; Scholze, Stefan; Höppner, Sebastian; Ellguth, Georg; Schüffny, Rene

    2015-01-01

    Synaptic dynamics, such as long- and short-term plasticity, play an important role in the complexity and biological realism achievable when running neural networks on a neuromorphic IC. For example, they endow the IC with an ability to adapt and learn from its environment. In order to achieve the millisecond to second time constants required for these synaptic dynamics, analog subthreshold circuits are usually employed. However, due to process variation and leakage problems, it is almost impossible to port these types of circuits to modern sub-100nm technologies. In contrast, we present a neuromorphic system in a 28 nm CMOS process that employs switched capacitor (SC) circuits to implement 128 short term plasticity presynapses as well as 8192 stop-learning synapses. The neuromorphic system consumes an area of 0.36 mm2 and runs at a power consumption of 1.9 mW. The circuit makes use of a technique for minimizing leakage effects allowing for real-time operation with time constants up to several seconds. Since we rely on SC techniques for all calculations, the system is composed of only generic mixed-signal building blocks. These generic building blocks make the system easy to port between technologies and the large digital circuit part inherent in an SC system benefits fully from technology scaling. PMID:25698914

  1. Switched-capacitor realization of presynaptic short-term-plasticity and stop-learning synapses in 28 nm CMOS.

    PubMed

    Noack, Marko; Partzsch, Johannes; Mayr, Christian G; Hänzsche, Stefan; Scholze, Stefan; Höppner, Sebastian; Ellguth, Georg; Schüffny, Rene

    2015-01-01

    Synaptic dynamics, such as long- and short-term plasticity, play an important role in the complexity and biological realism achievable when running neural networks on a neuromorphic IC. For example, they endow the IC with an ability to adapt and learn from its environment. In order to achieve the millisecond to second time constants required for these synaptic dynamics, analog subthreshold circuits are usually employed. However, due to process variation and leakage problems, it is almost impossible to port these types of circuits to modern sub-100nm technologies. In contrast, we present a neuromorphic system in a 28 nm CMOS process that employs switched capacitor (SC) circuits to implement 128 short term plasticity presynapses as well as 8192 stop-learning synapses. The neuromorphic system consumes an area of 0.36 mm(2) and runs at a power consumption of 1.9 mW. The circuit makes use of a technique for minimizing leakage effects allowing for real-time operation with time constants up to several seconds. Since we rely on SC techniques for all calculations, the system is composed of only generic mixed-signal building blocks. These generic building blocks make the system easy to port between technologies and the large digital circuit part inherent in an SC system benefits fully from technology scaling. PMID:25698914

  2. Short-Term Plasticity of the Visuomotor Map during Grasping Movements in Humans

    ERIC Educational Resources Information Center

    Safstrom, Daniel; Edin, Benoni B.

    2005-01-01

    During visually guided grasping movements, visual information is transformed into motor commands. This transformation is known as the "visuomotor map." To investigate limitations in the short-term plasticity of the visuomotor map in normal humans, we studied the maximum grip aperture (MGA) during the reaching phase while subjects grasped objects…

  3. Persistent Associative Plasticity at an Identified Synapse Underlying Classical Conditioning Becomes Labile with Short-Term Homosynaptic Activation

    PubMed Central

    Schacher, Samuel

    2015-01-01

    Synapses express different forms of plasticity that contribute to different forms of memory, and both memory and plasticity can become labile after reactivation. We previously reported that a persistent form of nonassociative long-term facilitation (PNA-LTF) of the sensorimotor synapses in Aplysia californica, a cellular analog of long-term sensitization, became labile with short-term heterosynaptic reactivation and reversed when the reactivation was followed by incubation with the protein synthesis inhibitor rapamycin. Here we examined the reciprocal impact of different forms of short-term plasticity (reactivations) on a persistent form of associative long-term facilitation (PA-LTF), a cellular analog of classical conditioning, which was expressed at Aplysia sensorimotor synapses when a tetanic stimulation of the sensory neurons was paired with a brief application of serotonin on 2 consecutive days. The expression of short-term homosynaptic plasticity [post-tetanic potentiation or homosynaptic depression (HSD)], or short-term heterosynaptic plasticity [serotonin-induced facilitation or neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa)-induced depression], at synapses expressing PA-LTF did not affect the maintenance of PA-LTF. The kinetics of HSD was attenuated at synapses expressing PA-LTF, which required activation of protein kinase C (PKC). Both PA-LTF and the attenuated kinetics of HSD were reversed by either a transient blockade of PKC activity or a homosynaptic, but not heterosynaptic, reactivation when paired with rapamycin. These results indicate that two different forms of persistent synaptic plasticity, PA-LTF and PNA-LTF, expressed at the same synapse become labile when reactivated by different stimuli. SIGNIFICANCE STATEMENT Activity-dependent changes in neural circuits mediate long-term memories. Some forms of long-term memories become labile and can be reversed with specific types of reactivations, but the mechanism is complex. At the cellular level

  4. [Motor Proteins of Microtubules and Mechanisms of Synaptic Plasticity].

    PubMed

    Vasilyeva, N A; Pivovarov, A S

    2016-01-01

    Motor proteins of microtubules, kinesin and dynein superfamily proteins play an important role in the intracellular transport. Inside a neuron they are involved in the transport of organelles, proteins and mRNAs along the axons and dendrites to the nerve terminals and back to the cell bodies. Disturbance of axonal transport may affect neurotransmitter release and short-term presynaptic plasticity. Disturbance of dendritic transport, in particular the recycling of synaptic receptors, affects postsynaptic plasticity. The review attempts to trace the connections between the motor proteins of microtubules and mechanisms of synaptic plasticity from the perspective of their involvement in the intracellular transport of proteins and organelles, which play role in the mechanisms of synaptic plasticity. PMID:27538280

  5. Inhibitory short-term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro.

    PubMed

    Lavian, Hagar; Korngreen, Alon

    2016-04-01

    The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input-output transformation we performed whole-cell and perforated-patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short-term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short-term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter-spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low-frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high-frequency pallidal output may continuously modulate EP firing.

  6. Presynaptic Adenosine Receptor-Mediated Regulation of Diverse Thalamocortical Short-Term Plasticity in the Mouse Whisker Pathway

    PubMed Central

    Ferrati, Giovanni; Martini, Francisco J.; Maravall, Miguel

    2016-01-01

    Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In “driver” thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release. PMID:26941610

  7. Synaptic plasticity functions in an organic electrochemical transistor

    NASA Astrophysics Data System (ADS)

    Gkoupidenis, Paschalis; Schaefer, Nathan; Strakosas, Xenofon; Fairfield, Jessamyn A.; Malliaras, George G.

    2015-12-01

    Synaptic plasticity functions play a crucial role in the transmission of neural signals in the brain. Short-term plasticity is required for the transmission, encoding, and filtering of the neural signal, whereas long-term plasticity establishes more permanent changes in neural microcircuitry and thus underlies memory and learning. The realization of bioinspired circuits that can actually mimic signal processing in the brain demands the reproduction of both short- and long-term aspects of synaptic plasticity in a single device. Here, we demonstrate the implementation of neuromorphic functions similar to biological memory, such as short- to long-term memory transition, in non-volatile organic electrochemical transistors (OECTs). Depending on the training of the OECT, the device displays either short- or long-term plasticity, therefore, exhibiting non von Neumann characteristics with merged processing and storing functionalities. These results are a first step towards the implementation of organic-based neuromorphic circuits.

  8. Study of short-term plasticity in two contrasting genotypes of Populus nigra L.

    PubMed

    Russo, G; Sabatti, M; De Angelis, P

    2016-08-01

    Species like black poplar characterized by an indeterminate growth, can acclimate to the changing environmental conditions during the seasons through a modification of morphological and physiological features. The acclimation results fundamental for the increasing evapo-transpirative demand and water availability. In this perspective, each generation of leaf becomes an indicator of physiologic performance, determining the short-term plasticity (acclimation) of a genotype to different environmental conditions. The main objective of this work is to analyse the physiological adjustment by morphological and physiological features of leaves in two contrasting genotypes of Populus nigra L., growing in a common environment. The mesic genotype 58-861 (Northern Italy) reacts to the increasing dry conditions keeping constantly higher values of δ(13)C while the xeric genotype Poli (Southern Italy) shows lower values, despite no significant differences in the gas exchanges. Morphological and stomatal leaf traits were the main drivers of the different behaviour in the two genotypes to face the "temporal" environment, but different from the provenance. In particular the results, especially in the development phases, demonstrate how phenotypic plasticity is evident at seasonal scale, playing a role for the success of an indeterminate-growing species. They could also be generalized for similar experiments and could support further investigation about short-term plasticity. PMID:27295395

  9. Short-Term Plasticity of a Thalamocortical Pathway Dynamically Modulated by Behavioral State

    NASA Astrophysics Data System (ADS)

    Castro-Alamancos, Manuel A.; Connors, Barry W.

    1996-04-01

    The neocortex receives information about the environment and the rest of the brain through pathways from the thalamus. These pathways have frequency-dependent properties that can strongly influence their effect on the neocortex. In 1943 Morison and Dempsey described "augmenting responses," a form of short-term plasticity in some thalamocortical pathways that is triggered by 8- to 15-hertz activation. Results from anesthetized rats showed that the augmenting response is initiated by pyramidal cells in layer V. The augmenting response was also observed in awake, unrestrained animals and was found to be dynamically modulated by their behavioral state.

  10. Plastic mulching in agriculture. Trading short-term agronomic benefits for long-term soil degradation?

    PubMed

    Steinmetz, Zacharias; Wollmann, Claudia; Schaefer, Miriam; Buchmann, Christian; David, Jan; Tröger, Josephine; Muñoz, Katherine; Frör, Oliver; Schaumann, Gabriele Ellen

    2016-04-15

    Plastic mulching has become a globally applied agricultural practice for its instant economic benefits such as higher yields, earlier harvests, improved fruit quality and increased water-use efficiency. However, knowledge of the sustainability of plastic mulching remains vague in terms of both an environmental and agronomic perspective. This review critically discusses the current understanding of the environmental impact of plastic mulch use by linking knowledge of agricultural benefits and research on the life cycle of plastic mulches with direct and indirect implications for long-term soil quality and ecosystem services. Adverse effects may arise from plastic additives, enhanced pesticide runoff and plastic residues likely to fragment into microplastics but remaining chemically intact and accumulating in soil where they can successively sorb agrochemicals. The quantification of microplastics in soil remains challenging due to the lack of appropriate analytical techniques. The cost and effort of recovering and recycling used mulching films may offset the aforementioned benefits in the long term. However, comparative and long-term agronomic assessments have not yet been conducted. Furthermore, plastic mulches have the potential to alter soil quality by shifting the edaphic biocoenosis (e.g. towards mycotoxigenic fungi), accelerate C/N metabolism eventually depleting soil organic matter stocks, increase soil water repellency and favour the release of greenhouse gases. A substantial process understanding of the interactions between the soil microclimate, water supply and biological activity under plastic mulches is still lacking but required to estimate potential risks for long-term soil quality. Currently, farmers mostly base their decision to apply plastic mulches rather on expected short-term benefits than on the consideration of long-term consequences. Future interdisciplinary research should therefore gain a deeper understanding of the incentives for farmers

  11. Plastic mulching in agriculture. Trading short-term agronomic benefits for long-term soil degradation?

    PubMed

    Steinmetz, Zacharias; Wollmann, Claudia; Schaefer, Miriam; Buchmann, Christian; David, Jan; Tröger, Josephine; Muñoz, Katherine; Frör, Oliver; Schaumann, Gabriele Ellen

    2016-04-15

    Plastic mulching has become a globally applied agricultural practice for its instant economic benefits such as higher yields, earlier harvests, improved fruit quality and increased water-use efficiency. However, knowledge of the sustainability of plastic mulching remains vague in terms of both an environmental and agronomic perspective. This review critically discusses the current understanding of the environmental impact of plastic mulch use by linking knowledge of agricultural benefits and research on the life cycle of plastic mulches with direct and indirect implications for long-term soil quality and ecosystem services. Adverse effects may arise from plastic additives, enhanced pesticide runoff and plastic residues likely to fragment into microplastics but remaining chemically intact and accumulating in soil where they can successively sorb agrochemicals. The quantification of microplastics in soil remains challenging due to the lack of appropriate analytical techniques. The cost and effort of recovering and recycling used mulching films may offset the aforementioned benefits in the long term. However, comparative and long-term agronomic assessments have not yet been conducted. Furthermore, plastic mulches have the potential to alter soil quality by shifting the edaphic biocoenosis (e.g. towards mycotoxigenic fungi), accelerate C/N metabolism eventually depleting soil organic matter stocks, increase soil water repellency and favour the release of greenhouse gases. A substantial process understanding of the interactions between the soil microclimate, water supply and biological activity under plastic mulches is still lacking but required to estimate potential risks for long-term soil quality. Currently, farmers mostly base their decision to apply plastic mulches rather on expected short-term benefits than on the consideration of long-term consequences. Future interdisciplinary research should therefore gain a deeper understanding of the incentives for farmers

  12. Short-term plasticity regulates the E/I ratio and the temporal window for spike integration in CA1 pyramidal cells

    PubMed Central

    Bartley, Aundrea F.; Dobrunz, Lynn E.

    2016-01-01

    Many neurodevelopmental and neuropsychiatric disorders have an imbalance between excitation (E) and inhibition (I) caused by synaptic alterations. The proper E/I balance is especially critical in CA1 pyramidal cells because they control hippocampal output. Activation of Schaffer collateral axons causes direct excitation of CA1 pyramidal cells, quickly followed by disynaptic feed-forward inhibition, stemming from synaptically induced firing of GABAergic interneurons. Both excitatory and inhibitory synapses are modulated by short-term plasticity, potentially causing dynamic tuning of the E/I ratio. However, the effects of short-term plasticity on the E/I ratio in CA1 pyramidal cells are not yet known. To determine this we recorded disynaptic IPSCs and E/I ratio in CA1 pyramidal cells in acute hippocampal slices from juvenile mice. We find that while inhibitory synapses have paired-pulse depression, disynaptic inhibition instead expresses paired-pulse facilitation (≤ 200 ms intervals), caused by increased recruitment of feed-forward interneurons. Although enhanced disynaptic inhibition helps constrain paired-pulse facilitation of excitation, the E/I ratio is still larger on the second pulse, increasing pyramidal cell spiking. Surprisingly, this occurs without compromising the precision of spike timing. The E/I balance regulates the temporal spike integration window from multiple inputs; here we show that paired-pulse stimulation can broaden the spike integration window. Together, we find that the combined effects of short-term plasticity of disynaptic inhibition and monosynaptic excitation alter the E/I balance onto CA1 pyramidal cells, leading to dynamic modulation of spike probability and spike integration window. Short-term plasticity is therefore an important mechanism for modulating signal processing of hippocampal output. PMID:25903384

  13. Factors explaining heterogeneity in short-term synaptic dynamics of hippocampal glutamatergic synapses in the neonatal rat.

    PubMed

    Hanse, E; Gustafsson, B

    2001-11-15

    1. Quantal release from single hippocampal glutamatergic (CA3-CA1) synapses was examined in the neonatal rat during a 10 impulse, 50 Hz stimulus train. These synapses contain a single release site only, thus allowing for an analysis of frequency facilitation/depression at the single release site level. 2. These synapses displayed a considerable heterogeneity with respect to short-term synaptic dynamics, from a pronounced facilitation to a pronounced depression. Facilitation/depression was the same whether evaluated using the magnitude or the probability of occurrence of the postsynaptic response. This result suggests that postsynaptic factors, such as desensitisation, play little role. 3. Release probabilities initially and late during the train were uncorrelated. Initially, release is determined by the number of immediately release-ready vesicles and by the probability of releasing such vesicles (P(ves)). Within the first five stimuli this vesicle pool is depleted. The deciding factor for release is thereafter the rate at which new vesicles can be recruited for release, rather than P(ves). 4. Heterogeneity in facilitation/depression among the synapses was strongly correlated with heterogeneity in initial P(ves) but not with that of the immediately release-ready vesicle pool. Thus, the main factors deciding short-term synaptic dynamics are heterogeneity in initial P(ves) and in vesicle recruitment rate among the synapses.

  14. Unraveling mechanisms of homeostatic synaptic plasticity

    PubMed Central

    Pozo, Karine; Goda, Yukiko

    2011-01-01

    SUMMARY Homeostatic synaptic plasticity is a negative feedback mechanism neurons use to offset excessive excitation or inhibition by adjusting their synaptic strengths. Recent findings reveal a complex web of signaling processes involved in this compensatory form of synaptic strength regulation, and in contrast to the popular view of homeostatic plasticity as a slow, global phenomenon, neurons may also rapidly tune the efficacy of individual synapses on demand. Here we review our current understanding of cellular and molecular mechanisms of homeostatic synaptic plasticity. PMID:20471348

  15. Adult plasticity in multisensory neurons: Short-term experience-dependent changes in the superior colliculus

    PubMed Central

    Yu, Liping; Stein, Barry E.; Rowland, Benjamin A.

    2010-01-01

    Multisensory neurons in the superior colliculus (SC) have the capability to integrate signals that belong to the same event, despite being conveyed by different senses. They develop this capability during early life as experience is gained with the statistics of cross-modal events. These adaptations prepare the SC to deal with the cross-modal events that are likely to be encountered throughout life. Here we found that neurons in the adult SC can also adapt to experience with sequentially-ordered cross-modal (visual-auditory or auditory-visual) cues, and that they do so over short periods of time (minutes), as if adapting to a particular stimulus configuration. This short-term plasticity was evident as a rapid increase in the magnitude and duration of responses to the first stimulus, and a shortening of the latency and increase in magnitude of the responses to the second stimulus when they are presented in sequence. The result was that the two responses appeared to merge. These changes were stable in the absence of experience with competing stimulus configurations, outlasted the exposure period, and could not be induced by equivalent experience with sequential within-modal (visual-visual or auditory-auditory) stimuli. A parsimonious interpretation is that the additional SC activity provided by the second stimulus became associated with, and increased the potency of, the afferents responding to the preceding stimulus. This interpretation is consistent with the principle of spike-timing dependent plasticity (STDP), which may provide the basic mechanism for short term or long term plasticity and be operative in both the adult and neonatal SC. PMID:20016107

  16. Cortical plasticity induced by short-term unimodal and multimodal musical training.

    PubMed

    Lappe, Claudia; Herholz, Sibylle C; Trainor, Laurel J; Pantev, Christo

    2008-09-24

    Learning to play a musical instrument requires complex multimodal skills involving simultaneous perception of several sensory modalities: auditory, visual, somatosensory, as well as the motor system. Therefore, musical training provides a good and adequate neuroscientific model to study multimodal brain plasticity effects in humans. Here, we investigated the impact of short-term unimodal and multimodal musical training on brain plasticity. Two groups of nonmusicians were musically trained over the course of 2 weeks. One group [sensorimotor-auditory (SA)] learned to play a musical sequence on the piano, whereas the other group [auditory (A)] listened to and made judgments about the music that had been played by participants of the sensorimotor-auditory group. Training-induced cortical plasticity was assessed by recording the musically elicited mismatch negativity (MMNm) from magnetoencephalographic measurements before and after training. SA and A groups showed significantly different cortical responses after training. Specifically, the SA group showed significant enlargement of MMNm after training compared with the A group, reflecting greater enhancement of musical representations in auditory cortex after sensorimotor-auditory training compared with after mere auditory training. Thus, we have experimentally demonstrated that not only are sensorimotor and auditory systems connected, but also that sensorimotor-auditory training causes plastic reorganizational changes in the auditory cortex over and above changes introduced by auditory training alone.

  17. Heterogeneous mean field for neural networks with short-term plasticity

    NASA Astrophysics Data System (ADS)

    di Volo, Matteo; Burioni, Raffaella; Casartelli, Mario; Livi, Roberto; Vezzani, Alessandro

    2014-08-01

    We report about the main dynamical features of a model of leaky integrate-and-fire excitatory neurons with short-term plasticity defined on random massive networks. We investigate the dynamics by use of a heterogeneous mean-field formulation of the model that is able to reproduce dynamical phases characterized by the presence of quasisynchronous events. This formulation allows one to solve also the inverse problem of reconstructing the in-degree distribution for different network topologies from the knowledge of the global activity field. We study the robustness of this inversion procedure by providing numerical evidence that the in-degree distribution can be recovered also in the presence of noise and disorder in the external currents. Finally, we discuss the validity of the heterogeneous mean-field approach for sparse networks with a sufficiently large average in-degree.

  18. Short-term phenotypic plasticity in long-chain cuticular hydrocarbons.

    PubMed

    Thomas, Melissa L; Simmons, Leigh W

    2011-10-22

    Cuticular hydrocarbons provide arthropods with the chemical equivalent of the visually extravagant plumage of birds. Their long chain length, together with the number and variety of positions in which methyl branches and double bonds occur, provide cuticular hydrocarbons with an extraordinary level of information content. Here, we demonstrate phenotypic plasticity in an individual's cuticular hydrocarbon profile. Using solid-phase microextraction, a chemical technique that enables multiple sampling of the same individual, we monitor short-term changes in cuticular hydrocarbon profiles of individual crickets, Teleogryllus oceanicus, in response to a social challenge. We experimentally manipulate the dominance status of males and find that dominant males, on losing fights with other dominant males, change their hydrocarbon profile to more closely resemble that of a subordinate. This result demonstrates that cuticular hydrocarbons can be far more responsive to changes in social dominance than previously realized.

  19. Short-term phenotypic plasticity in long-chain cuticular hydrocarbons.

    PubMed

    Thomas, Melissa L; Simmons, Leigh W

    2011-10-22

    Cuticular hydrocarbons provide arthropods with the chemical equivalent of the visually extravagant plumage of birds. Their long chain length, together with the number and variety of positions in which methyl branches and double bonds occur, provide cuticular hydrocarbons with an extraordinary level of information content. Here, we demonstrate phenotypic plasticity in an individual's cuticular hydrocarbon profile. Using solid-phase microextraction, a chemical technique that enables multiple sampling of the same individual, we monitor short-term changes in cuticular hydrocarbon profiles of individual crickets, Teleogryllus oceanicus, in response to a social challenge. We experimentally manipulate the dominance status of males and find that dominant males, on losing fights with other dominant males, change their hydrocarbon profile to more closely resemble that of a subordinate. This result demonstrates that cuticular hydrocarbons can be far more responsive to changes in social dominance than previously realized. PMID:21367785

  20. The Role of NMDA Receptor Subtypes in Short-Term Plasticity in the Rat Entorhinal Cortex

    PubMed Central

    Chamberlain, Sophie E. L.; Yang, Jian; Jones, Roland S. G.

    2008-01-01

    We have previously shown that spontaneous release of glutamate in the entorhinal cortex (EC) is tonically facilitated via activation of presynaptic NMDA receptors (NMDAr) containing the NR2B subunit. Here we show that the same receptors mediate short-term plasticity manifested by frequency-dependent facilitation of evoked glutamate release at these synapses. Whole-cell patch-clamp recordings were made from layer V pyramidal neurones in rat EC slices. Evoked excitatory postsynaptic currents showed strong facilitation at relatively low frequencies (3 Hz) of activation. Facilitation was abolished by an NR2B-selective blocker (Ro 25-6981), but unaffected by NR2A-selective antagonists (Zn2+, NVP-AAM077). In contrast, postsynaptic NMDAr-mediated responses could be reduced by subunit-selective concentrations of all three antagonists. The data suggest that NMDAr involved in presynaptic plasticity in layer V are exclusively NR1/NR2B diheteromers, whilst postsynaptically they are probably a mixture of NR1/NR2A, NR1/NR2B diheteromers and NR1/NR2A/NR2B triheteromeric receptors. PMID:18989370

  1. A novel short-term plasticity of intrinsic excitability in the hippocampal CA1 pyramidal cells

    PubMed Central

    Sánchez-Aguilera, A; Sánchez-Alonso, J L; Vicente-Torres, M A; Colino, A

    2014-01-01

    Changes in neuronal activity often trigger compensatory mechanisms aimed at regulating network activity homeostatically. Here we have identified and characterized a novel form of compensatory short-term plasticity of membrane excitability, which develops early after the eye-opening period in rats (P16–19 days) but not before that developmental stage (P9–12 days old). Holding the membrane potential of CA1 neurons right below the firing threshold from 15 s to several minutes induced a potentiation of the repolarizing phase of the action potentials that contributed to a decrease in the firing rate of CA1 pyramidal neurons in vitro. Furthermore, the mechanism for inducing this plasticity required the action of intracellular Ca2+ entering through T-type Ca2+ channels. This increase in Ca2+ subsequently activated the Ca2+ sensor K+ channel interacting protein 3, which led to the increase of an A-type K+ current. These results suggest that Ca2+ modulation of somatic A-current represents a new form of homeostatic regulation that provides CA1 pyramidal neurons with the ability to preserve their firing abilities in response to membrane potential variations on a scale from tens of seconds to several minutes. PMID:24756640

  2. Cortical plasticity induced by short-term multimodal musical rhythm training.

    PubMed

    Lappe, Claudia; Trainor, Laurel J; Herholz, Sibylle C; Pantev, Christo

    2011-01-01

    Performing music is a multimodal experience involving the visual, auditory, and somatosensory modalities as well as the motor system. Therefore, musical training is an excellent model to study multimodal brain plasticity. Indeed, we have previously shown that short-term piano practice increase the magnetoencephalographic (MEG) response to melodic material in novice players. Here we investigate the impact of piano training using a rhythmic-focused exercise on responses to rhythmic musical material. Musical training with non musicians was conducted over a period of two weeks. One group (sensorimotor-auditory, SA) learned to play a piano sequence with a distinct musical rhythm, another group (auditory, A) listened to, and evaluated the rhythmic accuracy of the performances of the SA-group. Training-induced cortical plasticity was evaluated using MEG, comparing the mismatch negativity (MMN) in response to occasional rhythmic deviants in a repeating rhythm pattern before and after training. The SA-group showed a significantly greater enlargement of MMN and P2 to deviants after training compared to the A- group. The training-induced increase of the rhythm MMN was bilaterally expressed in contrast to our previous finding where the MMN for deviants in the pitch domain showed a larger right than left increase. The results indicate that when auditory experience is strictly controlled during training, involvement of the sensorimotor system and perhaps increased attentional recources that are needed in producing rhythms lead to more robust plastic changes in the auditory cortex compared to when rhythms are simply attended to in the auditory domain in the absence of motor production.

  3. Synaptic AMPA Receptor Plasticity and Behavior

    PubMed Central

    Kessels, Helmut W.; Malinow, Roberto

    2014-01-01

    The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors (AMPARs), respectively. We here present an overview of studies that have used animal models to show that such AMPAR trafficking underlies several experience-driven phenomena—from neuronal circuit formation to the modification of behavior. We argue that monitoring and manipulating synaptic AMPAR trafficking represents an attractive means to study cognitive function and dysfunction in animal models. PMID:19217372

  4. Balance and stability of synaptic structures during synaptic plasticity.

    PubMed

    Meyer, Daniel; Bonhoeffer, Tobias; Scheuss, Volker

    2014-04-16

    Subsynaptic structures such as bouton, active zone, postsynaptic density (PSD) and dendritic spine, are highly correlated in their dimensions and also correlate with synapse strength. Why this is so and how such correlations are maintained during synaptic plasticity remains poorly understood. We induced spine enlargement by two-photon glutamate uncaging and examined the relationship between spine, PSD, and bouton size by two-photon time-lapse imaging and electron microscopy. In enlarged spines the PSD-associated protein Homer1c increased rapidly, whereas the PSD protein PSD-95 increased with a delay and only in cases of persistent spine enlargement. In the case of nonpersistent spine enlargement, the PSD proteins remained unchanged or returned to their original level. The ultrastructure at persistently enlarged spines displayed matching dimensions of spine, PSD, and bouton, indicating their correlated enlargement. This supports a model in which balancing of synaptic structures is a hallmark for the stabilization of structural modifications during synaptic plasticity. PMID:24742464

  5. Model predictions of features in microsaccade-related neural responses in a feedforward network with short-term synaptic depression

    NASA Astrophysics Data System (ADS)

    Zhou, Jian-Fang; Yuan, Wu-Jie; Zhou, Zhao; Zhou, Changsong

    2016-02-01

    Recently, the significant microsaccade-induced neural responses have been extensively observed in experiments. To explore the underlying mechanisms of the observed neural responses, a feedforward network model with short-term synaptic depression has been proposed [Yuan, W.-J., Dimigen, O., Sommer, W. and Zhou, C. Front. Comput. Neurosci. 7, 47 (2013)]. The depression model not only gave an explanation for microsaccades in counteracting visual fading, but also successfully reproduced several microsaccade-related features in experimental findings. These results strongly suggest that, the depression model is very useful to investigate microsaccade-related neural responses. In this paper, by using the model, we extensively study and predict the dependance of microsaccade-related neural responses on several key parameters, which could be tuned in experiments. Particularly, we provide a significant prediction that microsaccade-related neural response also complies with the property “sharper is better” observed in many contexts in neuroscience. Importantly, the property exhibits a power-law relationship between the width of input signal and the responsive effectiveness, which is robust against many parameters in the model. By using mean field theory, we analytically investigate the robust power-law property. Our predictions would give theoretical guidance for further experimental investigations of the functional role of microsaccades in visual information processing.

  6. Priming of Short-Term Potentiation and Synaptic Tagging/Capture Mechanisms by Ryanodine Receptor Activation in Rat Hippocampal CA1

    ERIC Educational Resources Information Center

    Sajikumar, Sreedharan; Li, Qin; Abraham, Wickliffe C.; Xiao, Zhi Cheng

    2009-01-01

    Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic…

  7. Membrane-derived phospholipids control synaptic neurotransmission and plasticity.

    PubMed

    García-Morales, Victoria; Montero, Fernando; González-Forero, David; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Medialdea-Wandossell, María Jesús; Domínguez-Vías, Germán; García-Verdugo, José Manuel; Moreno-López, Bernardo

    2015-05-01

    Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

  8. Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity

    PubMed Central

    García-Morales, Victoria; Montero, Fernando; González-Forero, David; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Medialdea-Wandossell, María Jesús; Domínguez-Vías, Germán; García-Verdugo, José Manuel; Moreno-López, Bernardo

    2015-01-01

    Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron. PMID:25996636

  9. A Single Brief Burst Induces GluR1-Dependent Associative Short-Term Potentiation: A Potential Mechanism for Short-Term Memory

    ERIC Educational Resources Information Center

    Erickson, Martha A.; Maramara, Lauren A.; Lisman, John

    2010-01-01

    Recent work showed that short-term memory (STM) is selectively reduced in GluR1 knockout mice. This raises the possibility that a form of synaptic modification dependent on GluR1 might underlie STM. Studies of synaptic plasticity have shown that stimuli too weak to induce long-term potentiation induce short-term potentiation (STP), a phenomenon…

  10. Reactivation of stalled polyribosomes in synaptic plasticity.

    PubMed

    Graber, Tyson E; Hébert-Seropian, Sarah; Khoutorsky, Arkady; David, Alexandre; Yewdell, Jonathan W; Lacaille, Jean-Claude; Sossin, Wayne S

    2013-10-01

    Some forms of synaptic plasticity require rapid, local activation of protein synthesis. Although this is thought to reflect recruitment of mRNAs to free ribosomes, this would limit the speed and magnitude of translational activation. Here we provide compelling in situ evidence supporting an alternative model in which synaptic mRNAs are transported as stably paused polyribosomes. Remarkably, we show that metabotropic glutamate receptor activation allows the synthesis of proteins that lead to a functional long-term depression phenotype even when translation initiation has been greatly reduced. Thus, neurons evolved a unique mechanism to swiftly translate synaptic mRNAs into functional protein upon synaptic signaling using stalled polyribosomes to bypass the rate-limiting step of translation initiation. Because dysregulated plasticity is implicated in neurodevelopmental and psychiatric disorders such as fragile X syndrome, this work uncovers a unique translational target for therapies.

  11. Constraints, independence, and evolution of thermal plasticity: probing genetic architecture of long- and short-term thermal acclimation.

    PubMed

    Gerken, Alison R; Eller, Olivia C; Hahn, Daniel A; Morgan, Theodore J

    2015-04-01

    Seasonal and daily thermal variation can limit species distributions because of physiological tolerances. Low temperatures are particularly challenging for ectotherms, which use both basal thermotolerance and acclimation, an adaptive plastic response, to mitigate thermal stress. Both basal thermotolerance and acclimation are thought to be important for local adaptation and persistence in the face of climate change. However, the evolutionary independence of basal and plastic tolerances remains unclear. Acclimation can occur over longer (seasonal) or shorter (hours to days) time scales, and the degree of mechanistic overlap is unresolved. Using a midlatitude population of Drosophila melanogaster, we show substantial heritable variation in both short- and long-term acclimation. Rapid cold hardening (short-term plasticity) and developmental acclimation (long-term plasticity) are positively correlated, suggesting shared mechanisms. However, there are independent components of these traits, because developmentally acclimated flies respond positively to short-term acclimation. A strong negative correlation between basal cold tolerance and developmental acclimation suggests that basal cold tolerance may constrain developmental acclimation, whereas a weaker negative correlation between basal cold tolerance and short-term acclimation suggests less constraint. Using genome-wide association mapping, we show the genetic architecture of rapid cold hardening and developmental acclimation responses are nonoverlapping at the SNP and corresponding gene level. However, genes associated with each trait share functional similarities, including genes involved in apoptosis and autophagy, cytoskeletal and membrane structural components, and ion binding and transport. These results indicate substantial opportunity for short-term and long-term acclimation responses to evolve separately from each other and for short-term acclimation to evolve separately from basal thermotolerance.

  12. Synaptic Vesicle Proteins and Active Zone Plasticity.

    PubMed

    Kittel, Robert J; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

  13. Synaptic Vesicle Proteins and Active Zone Plasticity

    PubMed Central

    Kittel, Robert J.; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention. PMID:27148040

  14. The Corticohippocampal Circuit, Synaptic Plasticity, and Memory.

    PubMed

    Basu, Jayeeta; Siegelbaum, Steven A

    2015-11-02

    Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC-hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories.

  15. Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

    PubMed Central

    Chen, Jen-Yung; Lonjers, Peter; Lee, Christopher; Chistiakova, Marina; Volgushev, Maxim

    2013-01-01

    Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity—Hebbian and heterosynaptic—may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories. PMID:24089497

  16. Network processes involved in the mediation of short-term habituation in Aplysia: contribution of intrinsic regulation of excitability and synaptic augmentation.

    PubMed

    Fischer, Thomas M; Jacobson, Daniel A; Demorest-Hayes, Kristin

    2014-01-01

    Short-term habituation (STH) is the decrease in behavioral responding observed during repeated stimulation at regular intervals. For siphon-elicited siphon withdrawal in Aplysia (S-SWR), we previously showed that the amplitude of responses measured in LFS-type siphon motor neurons (LFS MNs) during training is dependent on the stimulus interval used and is training-site specific. The major source of excitation from siphon stimulation onto the LFS MNs comes from the L29 interneurons. Here we examined the role of the L29s in STH by addressing two questions: (1) What are the relative contributions of intrinsic regulation of excitability and network inhibition on L29 activity during STH training? By activating L29s with intracellular current injection, we found that intrinsic changes in excitability occur, but only at short training intervals (1 s). We also demonstrated that network inhibition is not required for regulating L29 responses during training, indicating that any expression of inhibition is redundant to the excitability changes. (2) How does L29 synaptic plasticity contribute to the maintenance of training site-specificity exhibited in LFS MNs? When training stimuli are delivered 1 s apart [1 s, interstimulus interval (ISI)], L29 responses decrease in both stimulated (trained) and un-stimulated (untrained) pathways, yet site-specificity of training is maintained in the LFS MNs. Our results suggest that activity-dependent synaptic facilitation (augmentation; AUG) expressed by the L29s acts to compensate for the decreased activity in the untrained pathway. First, we demonstrated that the L29-LFS synapse exhibits significant AUG with L29 activation at a 1 s ISI. Second, we showed that the induction of AUG prevents the reduction in siphon-evoked LFS responses that is otherwise observed with decreased L29 activity. Collectively, our results support a role for the L29s in regulating network dynamics during STH training, but only at rapid (1 s ISI) training

  17. The transformation of synaptic to system plasticity in motor output from the sacral cord of the adult mouse.

    PubMed

    Jiang, Mingchen C; Elbasiouny, Sherif M; Collins, William F; Heckman, C J

    2015-09-01

    Synaptic plasticity is fundamental in shaping the output of neural networks. The transformation of synaptic plasticity at the cellular level into plasticity at the system level involves multiple factors, including behavior of local networks of interneurons. Here we investigate the synaptic to system transformation for plasticity in motor output in an in vitro preparation of the adult mouse spinal cord. System plasticity was assessed from compound action potentials (APs) in spinal ventral roots, which were generated simultaneously by the axons of many motoneurons (MNs). Synaptic plasticity was assessed from intracellular recordings of MNs. A computer model of the MN pool was used to identify the middle steps in the transformation from synaptic to system behavior. Two input systems that converge on the same MN pool were studied: one sensory and one descending. The two synaptic input systems generated very different motor outputs, with sensory stimulation consistently evoking short-term depression (STD) whereas descending stimulation had bimodal plasticity: STD at low frequencies but short-term facilitation (STF) at high frequencies. Intracellular and pharmacological studies revealed contributions from monosynaptic excitation and stimulus time-locked inhibition but also considerable asynchronous excitation sustained from local network activity. The computer simulations showed that STD in the monosynaptic excitatory input was the primary driver of the system STD in the sensory input whereas network excitation underlies the bimodal plasticity in the descending system. These results provide insight on the roles of plasticity in the monosynaptic and polysynaptic inputs converging on the same MN pool to overall motor plasticity.

  18. Fast Learning with Weak Synaptic Plasticity.

    PubMed

    Yger, Pierre; Stimberg, Marcel; Brette, Romain

    2015-09-30

    New sensory stimuli can be learned with a single or a few presentations. Similarly, the responses of cortical neurons to a stimulus have been shown to increase reliably after just a few repetitions. Long-term memory is thought to be mediated by synaptic plasticity, but in vitro experiments in cortical cells typically show very small changes in synaptic strength after a pair of presynaptic and postsynaptic spikes. Thus, it is traditionally thought that fast learning requires stronger synaptic changes, possibly because of neuromodulation. Here we show theoretically that weak synaptic plasticity can, in fact, support fast learning, because of the large number of synapses N onto a cortical neuron. In the fluctuation-driven regime characteristic of cortical neurons in vivo, the size of membrane potential fluctuations grows only as √N, whereas a single output spike leads to potentiation of a number of synapses proportional to N. Therefore, the relative effect of a single spike on synaptic potentiation grows as √N. This leverage effect requires precise spike timing. Thus, the large number of synapses onto cortical neurons allows fast learning with very small synaptic changes. Significance statement: Long-term memory is thought to rely on the strengthening of coactive synapses. This physiological mechanism is generally considered to be very gradual, and yet new sensory stimuli can be learned with just a few presentations. Here we show theoretically that this apparent paradox can be solved when there is a tight balance between excitatory and inhibitory input. In this case, small synaptic modifications applied to the many synapses onto a given neuron disrupt that balance and produce a large effect even for modifications induced by a single stimulus. This effect makes fast learning possible with small synaptic changes and reconciles physiological and behavioral observations.

  19. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity

    PubMed Central

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins. PMID:27630986

  20. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity

    PubMed Central

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

  1. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity.

    PubMed

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins. PMID:27630986

  2. Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

    PubMed

    O'Mara, S M; Commins, S; Anderson, M

    2000-01-01

    This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

  3. The amygdala, synaptic plasticity, and fear memory.

    PubMed

    Maren, Stephen

    2003-04-01

    The nature and mechanisms of synaptic plasticity in the amygdala and the relation of amygdaloid plasticity to behavior are exciting new areas of study in neuroscience. These issues were at the heart of presentations by Paul Chapman, Michael Fanselow, Patricia Shinnick-Gallagher, and Michael Rogawski in a session entitled "Long-Term Plasticity in Amygdala Synaptic Transmission" that was held at the conference featured in this volume. In this chapter, I briefly summarize these talks and give my perspective on the presentations as the session chair. I argue that we must first understand the role of the amygdala in learning and memory in order to understand the contribution of amygdaloid synaptic plasticity to behavior. Although it is generally agreed that the amygdala is involved in several forms of emotional learning and memory such as pavlovian fear conditioning, a recent debate has emerged concerning the precise role of the amygdala in learning versus performing fear responses. I discuss data from my laboratory that unravel this issue. I argue that the basolateral complex of the amygdala (BLA) normally plays an essential role in associative processes in fear conditioning. Nonetheless, rats with BLA lesions acquire and express conditional fear under some conditions. A neuroanatomical model that accounts for these data is presented.

  4. Regulation of hippocampal synaptic plasticity by BDNF.

    PubMed

    Leal, Graciano; Afonso, Pedro M; Salazar, Ivan L; Duarte, Carlos B

    2015-09-24

    The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of activity-dependent plasticity at excitatory synapses in the mammalian central nervous system. In particular, much attention has been given to the role of the neurotrophin in the regulation of hippocampal long-term potentiation (LTP), a sustained enhancement of excitatory synaptic strength believed to underlie learning and memory processes. In this review we summarize the evidence pointing to a role for BDNF in generating functional and structural changes at synapses required for both early- and late phases of LTP in the hippocampus. The available information regarding the pre- and/or postsynaptic release of BDNF and action of the neurotrophin during LTP will be also reviewed. Finally, we discuss the effects of BDNF on the synaptic proteome, either by acting on the protein synthesis machinery and/or by regulating protein degradation by calpains and possibly by the ubiquitin-proteasome system (UPS). This fine-tuned control of the synaptic proteome rather than a simple upregulation of the protein synthesis may play a key role in BDNF-mediated synaptic potentiation. This article is part of a Special Issue entitled SI: Brain and Memory. PMID:25451089

  5. Distinct short-term plasticity at two excitatory synapses in the hippocampus

    PubMed Central

    Salin, Paul A.; Scanziani, Massimo; Malenka, Robert C.; Nicoll, Roger A.

    1996-01-01

    A single mossy fiber input contains several release sites and is located on the proximal portion of the apical dendrite of CA3 neurons. It is, therefore, well suited to exert a strong influence on pyramidal cell excitability. Accordingly, the mossy fiber synapse has been referred to as a detonator or teacher synapse in autoassociative network models of the hippocampus. The very low firing rates of granule cells [Jung, M. W. & McNaughton, B. L. (1993) Hippocampus 3, 165–182], which give rise to the mossy fibers, raise the question of how the mossy fiber synapse temporally integrates synaptic activity. We have therefore addressed the frequency dependence of mossy fiber transmission and compared it to associational/commissural synapses in the CA3 region of the hippocampus. Paired pulse facilitation had a similar time course, but was 2-fold greater for mossy fiber synapses. Frequency facilitation, during which repetitive stimulation causes a reversible growth in synaptic transmission, was markedly different at the two synapses. At associational/commissural synapses facilitation occurred only at frequencies greater than once every 10 s and reached a magnitude of about 125% of control. At mossy fiber synapses, facilitation occurred at frequencies as low as once every 40 s and reached a magnitude of 6-fold. Frequency facilitation was dependent on a rise in intraterminal Ca2+ and activation of Ca2+/calmodulin-dependent kinase II, and was greatly reduced at synapses expressing mossy fiber long-term potentiation. These results indicate that the mossy fiber synapse is able to integrate granule cell spiking activity over a broad range of frequencies, and this dynamic range is substantially reduced by long-term potentiation. PMID:8917586

  6. Distinct short-term plasticity at two excitatory synapses in the hippocampus.

    PubMed

    Salin, P A; Scanziani, M; Malenka, R C; Nicoll, R A

    1996-11-12

    A single mossy fiber input contains several release sites and is located on the proximal portion of the apical dendrite of CA3 neurons. It is, therefore, well suited to exert a strong influence on pyramidal cell excitability. Accordingly, the mossy fiber synapse has been referred to as a detonator or teacher synapse in autoassociative network models of the hippocampus. The very low firing rates of granule cells [Jung, M. W. & McNaughton, B. L. (1993) Hippocampus 3, 165-182], which give rise to the mossy fibers, raise the question of how the mossy fiber synapse temporally integrates synaptic activity. We have therefore addressed the frequency dependence of mossy fiber transmission and compared it to associational/commissural synapses in the CA3 region of the hippocampus. Paired pulse facilitation had a similar time course, but was 2-fold greater for mossy fiber synapses. Frequency facilitation, during which repetitive stimulation causes a reversible growth in synaptic transmission, was markedly different at the two synapses. At associational/ commissural synapses facilitation occurred only at frequencies greater than once every 10 s and reached a magnitude of about 125% of control. At mossy fiber synapses, facilitation occurred at frequencies as low as once every 40 s and reached a magnitude of 6-fold. Frequency facilitation was dependent on a rise in intraterminal Ca2+ and activation of Ca2+/calmodulin-dependent kinase II, and was greatly reduced at synapses expressing mossy fiber long-term potentiation. These results indicate that the mossy fiber synapse is able to integrate granule cell spiking activity over a broad range of frequencies, and this dynamic range is substantially reduced by long-term potentiation.

  7. Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels.

    PubMed

    Schreiber, Joerg; Végh, Marlene J; Dawitz, Julia; Kroon, Tim; Loos, Maarten; Labonté, Dorthe; Li, Ka Wan; Van Nierop, Pim; Van Diepen, Michiel T; De Zeeuw, Chris I; Kneussel, Matthias; Meredith, Rhiannon M; Smit, August B; Van Kesteren, Ronald E

    2015-11-01

    Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3(-/-) mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity. PMID:26527743

  8. Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

    PubMed Central

    Schreiber, Joerg; Végh, Marlene J.; Dawitz, Julia; Kroon, Tim; Loos, Maarten; Labonté, Dorthe; Li, Ka Wan; Van Nierop, Pim; Van Diepen, Michiel T.; De Zeeuw, Chris I.; Kneussel, Matthias; Meredith, Rhiannon M.; Smit, August B.

    2015-01-01

    Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3−/− mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity. PMID:26527743

  9. Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex.

    PubMed

    Oswald, Anne-Marie M; Urban, Nathaniel N

    2012-05-01

    Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here, we demonstrate how the timescales associated with respiratory frequency, spike timing, and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase-locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex.

  10. Morphological plasticity of astroglia: Understanding synaptic microenvironment

    PubMed Central

    2015-01-01

    Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use‐dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015;63:2133–2151 PMID:25782611

  11. Endocannabinoids in Synaptic Plasticity and Neuroprotection

    PubMed Central

    Xu, Jian-Yi; Chen, Chu

    2014-01-01

    Endocannabinoids (eCBs) are endogenous lipid mediators involved in a variety of physiological, pharmacological, and pathological processes. While activation of the eCB system primarily induces inhibitory effects on both GABAergic and glutamatergic synaptic transmission and plasticity through acting on presynaptically-expressed CB1 receptors in the brain, accumulated information suggests that eCB signaling is also capable of facilitating or potentiating excitatory synaptic transmission in the hippocampus. Recent studies show that a long-lasting potentiation of excitatory synaptic transmission at Schaffer collateral (SC)-CA1 synapses is induced by spatiotemporally primed inputs, accompanying with a long-term depression of inhibitory synaptic transmission (I-LTD) in hippocampal CA1 pyramidal neurons. This input-timing-dependent long-lasting synaptic potentiation at SC-CA1 synapses is mediated by 2-arachidonoylglycerol (2-AG) signaling triggered by activation of postsynaptic NMDA receptors, group I metabotropic glutamate receptors (mGluRs), and a concurrent rise in intracellular Ca2+. Emerging evidence now also indicates that 2-AG is an important signaling mediator keeping brain homeostasis by exerting its anti-inflammatory and neuroprotective effects in response to harmful insults through CB1/2 receptor-dependent and/or independent mechanisms. Activation of the nuclear receptor protein peroxisome proliferator-activated receptor-γ (PPARγ) apparently is one of the important mechanisms in resolving neuroinflammation and protecting neurons produced by 2-AG signaling. Thus, the information summarized in this review suggests that the role of eCB signaling in maintaining integrity of brain function is greater than what we thought previously. PMID:24571856

  12. Computational Neuroscience: Modeling the Systems Biology of Synaptic Plasticity

    PubMed Central

    Kotaleski, Jeanette Hellgren; Blackwell, Kim T.

    2016-01-01

    Preface Synaptic plasticity is a mechanism proposed to underlie learning and memory. The complexity of the interactions between ion channels, enzymes, and genes involved in synaptic plasticity impedes a deep understanding of this phenomenon. Computer modeling is an approach to investigate the information processing that is performed by signaling pathways underlying synaptic plasticity. In the past few years, new software developments that blend computational neuroscience techniques with systems biology techniques have allowed large-scale, quantitative modeling of synaptic plasticity in neurons. We highlight significant advancements produced by these modeling efforts and introduce promising approaches that utilize advancements in live cell imaging. PMID:20300102

  13. Synaptic Plasticity, a Symphony in GEF

    PubMed Central

    2010-01-01

    Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the mammalian forebrain. While many spines display great stability, others change shape in a matter of seconds to minutes. These rapid alterations in dendritic spine number and size require tight control of the actin cytoskeleton, the main structural component of dendritic spines. The ability of neurons to alter spine number and size is essential for the expression of neuronal plasticity. Within spines, guanine nucleotide exchange factors (GEFs) act as critical regulators of the actin cytoskeleton by controlling the activity of Rho-GTPases. In this review, we focus on the Rho-GEFs expressed in the nucleus accumbens and localized to the postsynaptic density and, thus, positioned to effect rapid alterations in the structure of dendritic spines. We review literature that ties these GEFs to different receptor systems and intracellular signaling cascades and discuss the effects these interactions are likely to have on synaptic plasticity. PMID:20543890

  14. In Vitro Investigation of Synaptic Plasticity.

    PubMed

    Abrahamsson, Therese; Lalanne, Txomin; Watt, Alanna J; Sjöström, P Jesper

    2016-01-01

    A classical in vitro model for investigation of information storage in the brain is based on the acute hippocampal slice. Here, repeated high-frequency stimulation of excitatory Schaeffer collaterals making synapses onto pyramidal cells in the hippocampal CA1 region leads to strengthening of evoked field-recording responses-long-term potentiation (LTP)-in keeping with Hebb's postulate. This model remains tremendously influential for its reliability, specificity, and relative ease of use. More recent plasticity studies have explored various other brain regions including the neocortex, which often requires more laborious whole-cell recordings of synaptically connected pairs of neurons, to ensure that the identities of recorded cells are known. In addition, with this experimental approach, the spiking activity can be controlled with millisecond precision, which is necessary for the study of spike-timing-dependent plasticity (STDP). Here, we provide protocols for in vitro study of hippocampal CA1 LTP using field recordings, and of STDP in synaptically connected pairs of layer-5 pyramidal cells in acute slices of rodent neocortex. PMID:27250951

  15. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

    PubMed Central

    Arendt, Kristin L.; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M.; Tang, Yitai; Cho, Ahryon; Graef, Isabella A.; Chen, Lu

    2015-01-01

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID:26443861

  16. Role of MicroRNA in Governing Synaptic Plasticity

    PubMed Central

    2016-01-01

    Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases. PMID:27034846

  17. Memory capacities for synaptic and structural plasticity.

    PubMed

    Knoblauch, Andreas; Palm, Günther; Sommer, Friedrich T

    2010-02-01

    Neural associative networks with plastic synapses have been proposed as computational models of brain functions and also for applications such as pattern recognition and information retrieval. To guide biological models and optimize technical applications, several definitions of memory capacity have been used to measure the efficiency of associative memory. Here we explain why the currently used performance measures bias the comparison between models and cannot serve as a theoretical benchmark. We introduce fair measures for information-theoretic capacity in associative memory that also provide a theoretical benchmark. In neural networks, two types of manipulating synapses can be discerned: synaptic plasticity, the change in strength of existing synapses, and structural plasticity, the creation and pruning of synapses. One of the new types of memory capacity we introduce permits quantifying how structural plasticity can increase the network efficiency by compressing the network structure, for example, by pruning unused synapses. Specifically, we analyze operating regimes in the Willshaw model in which structural plasticity can compress the network structure and push performance to the theoretical benchmark. The amount C of information stored in each synapse can scale with the logarithm of the network size rather than being constant, as in classical Willshaw and Hopfield nets (< or = ln 2 approximately 0.7). Further, the review contains novel technical material: a capacity analysis of the Willshaw model that rigorously controls for the level of retrieval quality, an analysis for memories with a nonconstant number of active units (where C < or = 1/e ln 2 approximately 0.53), and the analysis of the computational complexity of associative memories with and without network compression.

  18. Alternative roles for Cdk5 in learning and synaptic plasticity.

    PubMed

    Hawasli, Ammar H; Bibb, James A

    2007-08-01

    Protein kinases mediate the intracellular signal transduction pathways controlling synaptic plasticity in the central nervous system. While the majority of protein kinases achieve this function via the phosphorylation of synaptic substrates, some kinases may contribute through alternative mechanisms in addition to enzymatic activity. There is growing evidence that protein kinases may often play structural roles in plasticity as well. Cyclin-dependent kinase 5 (Cdk5) has been implicated in learning and synaptic plasticity. Initial scrutiny focused on its enzymatic activity using pharmacological inhibitors and genetic modifications of Cdk5 cofactors. Quite recently Cdk5 has been shown to govern learning and plasticity via regulation of glutamate receptor degradation, a function that may not dependent on phosphorylation of downstream effectors. From these new studies, two roles emerge for Cdk5 in plasticity: one in which it controls structural plasticity via phosphorylation of synaptic substrates, and a second where it regulates functional plasticity via protein-protein interactions.

  19. The transformation of synaptic to system plasticity in motor output from the sacral cord of the adult mouse.

    PubMed

    Jiang, Mingchen C; Elbasiouny, Sherif M; Collins, William F; Heckman, C J

    2015-09-01

    Synaptic plasticity is fundamental in shaping the output of neural networks. The transformation of synaptic plasticity at the cellular level into plasticity at the system level involves multiple factors, including behavior of local networks of interneurons. Here we investigate the synaptic to system transformation for plasticity in motor output in an in vitro preparation of the adult mouse spinal cord. System plasticity was assessed from compound action potentials (APs) in spinal ventral roots, which were generated simultaneously by the axons of many motoneurons (MNs). Synaptic plasticity was assessed from intracellular recordings of MNs. A computer model of the MN pool was used to identify the middle steps in the transformation from synaptic to system behavior. Two input systems that converge on the same MN pool were studied: one sensory and one descending. The two synaptic input systems generated very different motor outputs, with sensory stimulation consistently evoking short-term depression (STD) whereas descending stimulation had bimodal plasticity: STD at low frequencies but short-term facilitation (STF) at high frequencies. Intracellular and pharmacological studies revealed contributions from monosynaptic excitation and stimulus time-locked inhibition but also considerable asynchronous excitation sustained from local network activity. The computer simulations showed that STD in the monosynaptic excitatory input was the primary driver of the system STD in the sensory input whereas network excitation underlies the bimodal plasticity in the descending system. These results provide insight on the roles of plasticity in the monosynaptic and polysynaptic inputs converging on the same MN pool to overall motor plasticity. PMID:26203107

  20. Fast response and high sensitivity to microsaccades in a cascading-adaptation neural network with short-term synaptic depression

    NASA Astrophysics Data System (ADS)

    Yuan, Wu-Jie; Zhou, Jian-Fang; Zhou, Changsong

    2016-04-01

    Microsaccades are very small eye movements during fixation. Experimentally, they have been found to play an important role in visual information processing. However, neural responses induced by microsaccades are not yet well understood and are rarely studied theoretically. Here we propose a network model with a cascading adaptation including both retinal adaptation and short-term depression (STD) at thalamocortical synapses. In the neural network model, we compare the microsaccade-induced neural responses in the presence of STD and those without STD. It is found that the cascading with STD can give rise to faster and sharper responses to microsaccades. Moreover, STD can enhance response effectiveness and sensitivity to microsaccadic spatiotemporal changes, suggesting improved detection of small eye movements (or moving visual objects). We also explore the mechanism of the response properties in the model. Our studies strongly indicate that STD plays an important role in neural responses to microsaccades. Our model considers simultaneously retinal adaptation and STD at thalamocortical synapses in the study of microsaccade-induced neural activity, and may be useful for further investigation of the functional roles of microsaccades in visual information processing.

  1. Fast response and high sensitivity to microsaccades in a cascading-adaptation neural network with short-term synaptic depression.

    PubMed

    Yuan, Wu-Jie; Zhou, Jian-Fang; Zhou, Changsong

    2016-04-01

    Microsaccades are very small eye movements during fixation. Experimentally, they have been found to play an important role in visual information processing. However, neural responses induced by microsaccades are not yet well understood and are rarely studied theoretically. Here we propose a network model with a cascading adaptation including both retinal adaptation and short-term depression (STD) at thalamocortical synapses. In the neural network model, we compare the microsaccade-induced neural responses in the presence of STD and those without STD. It is found that the cascading with STD can give rise to faster and sharper responses to microsaccades. Moreover, STD can enhance response effectiveness and sensitivity to microsaccadic spatiotemporal changes, suggesting improved detection of small eye movements (or moving visual objects). We also explore the mechanism of the response properties in the model. Our studies strongly indicate that STD plays an important role in neural responses to microsaccades. Our model considers simultaneously retinal adaptation and STD at thalamocortical synapses in the study of microsaccade-induced neural activity, and may be useful for further investigation of the functional roles of microsaccades in visual information processing. PMID:27176307

  2. Transient ECM protease activity promotes synaptic plasticity

    PubMed Central

    Magnowska, Marta; Gorkiewicz, Tomasz; Suska, Anna; Wawrzyniak, Marcin; Rutkowska-Wlodarczyk, Izabela; Kaczmarek, Leszek; Wlodarczyk, Jakub

    2016-01-01

    Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; however, excessive proteolytic activity is detrimental to the cells. The exact mechanism of control of these seemingly contradictory outcomes of protease activity remains unknown. Here, we reveal that dendritic spine maturation is strictly controlled by the proteolytic activity, and its inhibition by the endogenous inhibitor (Tissue inhibitor of matrix metalloproteinases-1 – TIMP-1). Excessive proteolytic activity impairs long-term potentiation of the synaptic efficacy (LTP), and this impairment could be rescued by inhibition of protease activity. Moreover LTP is altered persistently when the ability of TIMP-1 to inhibit protease activity is abrogated, further demonstrating the role of such inhibition in the promotion of synaptic plasticity under well-defined conditions. We also show that dendritic spine maturation involves an intermediate formation of elongated spines, followed by their conversion into mushroom shape. The formation of mushroom-shaped spines is accompanied by increase in AMPA/NMDA ratio of glutamate receptors. Altogether, our results identify inhibition of protease activity as a critical regulatory mechanism for dendritic spines maturation. PMID:27282248

  3. Short-Term Plasticity in a Monosynaptic Reflex Pathway to Forearm Muscles after Continuous Robot-Assisted Passive Stepping

    PubMed Central

    Nakajima, Tsuyoshi; Kamibayashi, Kiyotaka; Kitamura, Taku; Komiyama, Tomoyoshi; Zehr, E. Paul; Nakazawa, Kimitaka

    2016-01-01

    Both active and passive rhythmic limb movements reduce the amplitude of spinal cord Hoffmann (H-) reflexes in muscles of moving and distant limbs. This could have clinical utility in remote modulation of the pathologically hyperactive reflexes found in spasticity after stroke or spinal cord injury. However, such clinical translation is currently hampered by a lack of critical information regarding the minimum or effective duration of passive movement needed for modulating spinal cord excitability. We therefore investigated the H-reflex modulation in the flexor carpi radialis (FCR) muscle during and after various durations (5, 10, 15, and 30 min) of passive stepping in 11 neurologically normal subjects. Passive stepping was performed by a robotic gait trainer system (Lokomat®) while a single pulse of electrical stimulation to the median nerve elicited H-reflexes in the FCR. The amplitude of the FCR H-reflex was significantly suppressed during passive stepping. Although 30 min of passive stepping was sufficient to elicit a persistent H-reflex suppression that lasted up to 15 min, 5 min of passive stepping was not. The duration of H-reflex suppression correlated with that of the stepping. These findings suggest that the accumulation of stepping-related afferent feedback from the leg plays a role in generating short-term interlimb plasticity in the circuitry of the FCR H-reflex. PMID:27499737

  4. Short-Term Plasticity in a Monosynaptic Reflex Pathway to Forearm Muscles after Continuous Robot-Assisted Passive Stepping.

    PubMed

    Nakajima, Tsuyoshi; Kamibayashi, Kiyotaka; Kitamura, Taku; Komiyama, Tomoyoshi; Zehr, E Paul; Nakazawa, Kimitaka

    2016-01-01

    Both active and passive rhythmic limb movements reduce the amplitude of spinal cord Hoffmann (H-) reflexes in muscles of moving and distant limbs. This could have clinical utility in remote modulation of the pathologically hyperactive reflexes found in spasticity after stroke or spinal cord injury. However, such clinical translation is currently hampered by a lack of critical information regarding the minimum or effective duration of passive movement needed for modulating spinal cord excitability. We therefore investigated the H-reflex modulation in the flexor carpi radialis (FCR) muscle during and after various durations (5, 10, 15, and 30 min) of passive stepping in 11 neurologically normal subjects. Passive stepping was performed by a robotic gait trainer system (Lokomat(®)) while a single pulse of electrical stimulation to the median nerve elicited H-reflexes in the FCR. The amplitude of the FCR H-reflex was significantly suppressed during passive stepping. Although 30 min of passive stepping was sufficient to elicit a persistent H-reflex suppression that lasted up to 15 min, 5 min of passive stepping was not. The duration of H-reflex suppression correlated with that of the stepping. These findings suggest that the accumulation of stepping-related afferent feedback from the leg plays a role in generating short-term interlimb plasticity in the circuitry of the FCR H-reflex.

  5. Functional plasticity of sensorimotor representations following short-term immobilization of the dominant versus non-dominant hands.

    PubMed

    Meugnot, Aurore; Toussaint, Lucette

    2015-02-01

    The main purpose of the present study was to investigate the functional plasticity of sensorimotor representations for dominant versus non-dominant hands following short-term upper-limb sensorimotor deprivation. All participants were right-handed. A splint was placed either on the right hand or on the left hand of the participants during a brief period of 48 h and was used for the input/output signal restrictions. The participants were divided into 3 groups: right hand immobilization, left hand immobilization and control (without immobilization). The immobilized participants performed the hand laterality task before (pre-test) and immediately after (post-test) splint removal. The pre-/post-test procedure was similar for the control group. The main results showed a significant response time improvement when judging the laterality of hand stimuli in the control group. In contrast, the results showed a weaker response time improvement for the left-hand immobilization group and no significant improvement for the right-hand immobilization group. Overall, these results revealed that immobilization-induced effects were lower for the non-dominant hand and also suggested that 48 h of upper-limb immobilization led to an inter-limb transfer phenomenon regardless of the immobilized hand. The immobilization-induced effects were highlighted by the slowdown of the sensorimotor processes related to manual actions, probably due to an alteration in a general cognitive representation of hand movements.

  6. Facilitated CA1 hippocampal synaptic plasticity in dystrophin-deficient mice: role for GABAA receptors?

    PubMed

    Vaillend, Cyrille; Billard, Jean-Marie

    2002-01-01

    Duchenne muscular dystrophy (DMD) is associated with cognitive deficits that may result from a deficiency in the brain isoform of the cytoskeletal membrane-associated protein, dystrophin. CA1 hippocampal short-term potentiation (STP) of synaptic transmission is increased in dystrophin-deficient mdx mice, which has been attributed to a facilitated activation of NMDA receptors. In this study, extracellular recordings in the hippocampal slice preparation were used first to determine the consequences of this alteration on short-term depression (STD). STD induction was facilitated in mdx as compared with wild-type mice in a control medium. Because brain dystrophin deficiency results in a decreased number of gamma-aminobutyric acid A (GABAA)-receptor clusters, we tested the hypothesis that neuronal disinhibition contributes to the enhanced synaptic plasticity in mdx mice. We found that the GABAA receptor antagonist, bicuculline, increased basal neurotransmission in wild-type, but not in mdx mice and prevented the enhanced STP and STD in the CA1 area of slices from mdx mice. The possibility that altered GABA mechanisms underlie the facilitation of NMDA receptor-dependent synaptic plasticity in mdx mice is discussed.

  7. A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnOx-Al2O3 thin film structure

    NASA Astrophysics Data System (ADS)

    Li, H. K.; Chen, T. P.; Liu, P.; Hu, S. G.; Liu, Y.; Zhang, Q.; Lee, P. S.

    2016-06-01

    In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)-aluminum oxide (Al2O3) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al2O3 interface and/or in the Al2O3 layer.

  8. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    PubMed Central

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  9. Long-term Synaptic Plasticity: Circuit Perturbation and Stabilization

    PubMed Central

    Jung, Sung-Cherl; Eun, Su-Yong

    2014-01-01

    At central synapses, activity-dependent synaptic plasticity has a crucial role in information processing, storage, learning, and memory under both physiological and pathological conditions. One widely accepted model of learning mechanism and information processing in the brain is Hebbian Plasticity: long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are respectively activity-dependent enhancement and reduction in the efficacy of the synapses, which are rapid and synapse-specific processes. A number of recent studies have a strong focal point on the critical importance of another distinct form of synaptic plasticity, non-Hebbian plasticity. Non-Hebbian plasticity dynamically adjusts synaptic strength to maintain stability. This process may be very slow and occur cell-widely. By putting them all together, this mini review defines an important conceptual difference between Hebbian and non-Hebbian plasticity. PMID:25598658

  10. Matched pre- and post-synaptic changes underlie synaptic plasticity over long time scales.

    PubMed

    Loebel, Alex; Le Bé, Jean-Vincent; Richardson, Magnus J E; Markram, Henry; Herz, Andreas V M

    2013-04-10

    Modifications of synaptic efficacies are considered essential for learning and memory. However, it is not known how the underlying functional components of synaptic transmission change over long time scales. To address this question, we studied cortical synapses from young Wistar rats before and after 12 h intervals of spontaneous or glutamate-induced spiking activity. We found that, under these conditions, synaptic efficacies can increase or decrease by up to 10-fold. Statistical analyses reveal that these changes reflect modifications in the number of presynaptic release sites, together with postsynaptic changes that maintain the quantal size per release site. The quantitative relation between the presynaptic and postsynaptic transmission components was not affected when synaptic plasticity was enhanced or reduced using a broad range of pharmacological agents. These findings suggest that ongoing synaptic plasticity results in matched presynaptic and postsynaptic modifications, in which elementary modules that span the synaptic cleft are added or removed as a function of experience.

  11. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    ERIC Educational Resources Information Center

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  12. Mapping homeostatic synaptic plasticity using cable properties of dendrites.

    PubMed

    Queenan, B N; Lee, K J; Tan, H; Huganir, R L; Vicini, S; Pak, D T S

    2016-02-19

    When chronically silenced, cortical and hippocampal neurons homeostatically upregulate excitatory synaptic function. However, the subcellular position of such changes on the dendritic tree is not clear. We exploited the cable-filtering properties of dendrites to derive a parameter, the dendritic filtering index (DFI), to map the spatial distribution of synaptic currents. Our analysis indicates that young rat cortical neurons globally scale AMPA receptor-mediated currents, while mature hippocampal neurons do not, revealing distinct homeostatic strategies between brain regions and developmental stages. The DFI presents a useful tool for mapping the dendritic origin of synaptic currents and the location of synaptic plasticity changes.

  13. A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines

    PubMed Central

    Yang, Sunggu; Santos, Mariton D.; Tang, Cha-Min; Kim, Jae Geun; Yang, Sungchil

    2016-01-01

    Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation, short-term postsynaptic plasticity (STPP), has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain. PMID:27746721

  14. Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

    PubMed Central

    De Pittà, Maurizio; Brunel, Nicolas

    2016-01-01

    Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol. PMID:27195153

  15. In vivo long-term synaptic plasticity of glial cells.

    PubMed

    Bélair, Eve-Lyne; Vallée, Joanne; Robitaille, Richard

    2010-04-01

    Evidence showing the ability of glial cells to detect, respond to and modulate synaptic transmission and plasticity has contributed to the notion of glial cells as active synaptic partners. However, synaptically induced plasticity of glia themselves remains ill defined. Here we used the amphibian neuromuscular junction (NMJ) to study plasticity of perisynaptic Schwann cells (PSCs), glial cells at this synapse, following long-term in vivo modifications of synaptic activity. We used two models that altered synaptic activity in different manners. First, chronic blockade of postsynaptic nicotinic receptors using alpha-bungarotoxin (alpha-BTx) decreased facilitation, increased synaptic depression and decreased post-tetanic potentiation (PTP). Second, chronic nerve stimulation increased facilitation and resistance to synaptic depression, while leaving PTP unaltered. Our results indicate that there is no direct relationship between transmitter release and PSC calcium responses. Indeed, despite changes in transmitter release and plasticity in stimulated NMJs, nerve-evoked PSC calcium responses were similar to control. Similarly, PSC calcium responses in alpha-BTx treated NMJs were delayed and smaller in amplitude, even though basal level of transmitter release was increased. Also, when isolating purinergic and muscarinic components of PSC calcium responses, we found an increased sensitivity to ATP and a decreased sensitivity to muscarine in chronically stimulated NMJs. Conversely, in alpha-BTx treated NMJs, PSC sensitivity remained unaffected, but ATP- and muscarine-induced calcium responses were prolonged. Thus, our results reveal complex modifications of PSC properties, with differential modulation of signalling pathways that might underlie receptor regulation or changes in Ca(2+) handling. Importantly, similar to neurons, perisynaptic glial cells undergo plastic changes induced by altered synaptic activity.

  16. Synaptopodin regulates denervation-induced homeostatic synaptic plasticity

    PubMed Central

    Vlachos, Andreas; Ikenberg, Benno; Lenz, Maximilian; Becker, Denise; Reifenberg, Kurt; Bas-Orth, Carlos; Deller, Thomas

    2013-01-01

    Synaptopodin (SP) is a marker and essential component of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum that has been linked to synaptic plasticity. However, SP/SA-mediated synaptic plasticity remains incompletely understood. To study the role of SP/SA in homeostatic synaptic plasticity we here used denervation-induced synaptic scaling of mouse dentate granule cells as a model system. This form of plasticity is of considerable interest in the context of neurological diseases that are associated with the loss of neurons and subsequent denervation of connected brain regions. In entorhino-hippocampal slice cultures prepared from SP-deficient mice, which lack the SA, a compensatory increase in excitatory synaptic strength was not observed following partial deafferentation. In line with this finding, prolonged blockade of sodium channels with tetrodotoxin induced homeostatic synaptic scaling in wild-type, but not SP-deficient, slice cultures. By crossing SP-deficient mice with a newly generated transgenic mouse strain that expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP cluster size/stability and SA stack number, suggesting that activity-dependent SP/SA remodeling could be part of a negative feedback mechanism that aims at adjusting the strength of excitatory synapses to persisting changes in network activity. Thus, our results disclose an important role for SP/SA in homeostatic synaptic plasticity. PMID:23630268

  17. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

    PubMed Central

    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  18. Effect of acute fentanyl treatment on synaptic plasticity in the hippocampal CA1 region in rats

    PubMed Central

    Tian, Hai; Xu, Yueming; Liu, Fucun; Wang, Guowei; Hu, Sanjue

    2015-01-01

    Postoperative cognitive dysfunction (POCD), mainly characterized by short-term decline of learning and memory, occurs after operations under anesthesia. However, the underlying mechanisms are poorly understood. The μ-opioid receptors (MOR) are highly expressed in interneurons of hippocampus, and is believed to be critical for the dysfunction of synaptic plasticity between hippocampal neurons. Therefore, we investigated the effect of fentanyl, a strong agonist of MOR and often used for anesthesia and analgesia in clinical settings, on hippocampal synaptic plasticity in the Schaffer-collateral CA1 pathway during acute exposure and washout in vitro. Our results revealed that acute fentanyl exposure (0.01, 0.1, 1 μM) dose-dependently increased the field excitatory postsynaptic potentials (fEPSPs), which was prevented by pre-administration of picrotoxin (50 μM) or MOR antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 10 μM). While fentanyl exposure-increased fEPSPs amplitude was prevented by picrotoxin [an inhibitor of γ-aminobutyric acid receptor (GABAR)] treatment or fentanyl washout, pretreatment of picrotoxin failed to prevent the fentanyl-impaired long-term potentiation (LTP) of synaptic strength as well as the fentanyl-enhanced long-term depression (LTD). These results demonstrated that fentanyl acute exposure and washout increases hippocampal excitability in the Schaffer-collateral CA1 pathway, depending on disinhibiting interneurons after MOR activation. In addition, fentanyl acute exposure and washout modulated synaptic plasticity, but the inhibitory activation was not critical. Elucidating the detailed mechanisms for synaptic dysfunction after fentanyl exposure and washout may provide insights into POCD generation after fentanyl anesthesia. PMID:26578961

  19. Hebbian Wiring Plasticity Generates Efficient Network Structures for Robust Inference with Synaptic Weight Plasticity

    PubMed Central

    Hiratani, Naoki; Fukai, Tomoki

    2016-01-01

    In the adult mammalian cortex, a small fraction of spines are created and eliminated every day, and the resultant synaptic connection structure is highly nonrandom, even in local circuits. However, it remains unknown whether a particular synaptic connection structure is functionally advantageous in local circuits, and why creation and elimination of synaptic connections is necessary in addition to rich synaptic weight plasticity. To answer these questions, we studied an inference task model through theoretical and numerical analyses. We demonstrate that a robustly beneficial network structure naturally emerges by combining Hebbian-type synaptic weight plasticity and wiring plasticity. Especially in a sparsely connected network, wiring plasticity achieves reliable computation by enabling efficient information transmission. Furthermore, the proposed rule reproduces experimental observed correlation between spine dynamics and task performance. PMID:27303271

  20. Location-dependent synaptic plasticity rules by dendritic spine cooperativity.

    PubMed

    Weber, Jens P; Andrásfalvy, Bertalan K; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B; Makara, Judit K

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca(2+) signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca(2+) signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na(+) spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  1. Location-dependent synaptic plasticity rules by dendritic spine cooperativity

    PubMed Central

    Weber, Jens P.; Andrásfalvy, Bertalan K.; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B.; Makara, Judit K.

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca2+ signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca2+ signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na+ spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  2. Circuit reactivation dynamically regulates synaptic plasticity in neocortex

    NASA Astrophysics Data System (ADS)

    Kruskal, Peter B.; Li, Lucy; Maclean, Jason N.

    2013-10-01

    Circuit reactivations involve a stereotyped sequence of neuronal firing and have been behaviourally linked to memory consolidation. Here we use multiphoton imaging and patch-clamp recording, and observe sparse and stereotyped circuit reactivations that correspond to UP states within active neurons. To evaluate the effect of the circuit on synaptic plasticity, we trigger a single spike-timing-dependent plasticity (STDP) pairing once per circuit reactivation. The pairings reliably fall within a particular epoch of the circuit sequence and result in long-term potentiation. During reactivation, the amplitude of plasticity significantly correlates with the preceding 20-25 ms of membrane depolarization rather than the depolarization at the time of pairing. This circuit-dependent plasticity provides a natural constraint on synaptic potentiation, regulating the inherent instability of STDP in an assembly phase-sequence model. Subthreshold voltage during endogenous circuit reactivations provides a critical informative context for plasticity and facilitates the stable consolidation of a spatiotemporal sequence.

  3. Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity.

    PubMed

    Woolfrey, Kevin M; Dell'Acqua, Mark L

    2015-11-27

    A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity.

  4. Synaptic Plasticity Can Produce and Enhance Direction Selectivity

    PubMed Central

    Carver, Sean; Roth, Eatai; Cowan, Noah J; Fortune, Eric S

    2008-01-01

    The discrimination of the direction of movement of sensory images is critical to the control of many animal behaviors. We propose a parsimonious model of motion processing that generates direction selective responses using short-term synaptic depression and can reproduce salient features of direction selectivity found in a population of neurons in the midbrain of the weakly electric fish Eigenmannia virescens. The model achieves direction selectivity with an elementary Reichardt motion detector: information from spatially separated receptive fields converges onto a neuron via dynamically different pathways. In the model, these differences arise from convergence of information through distinct synapses that either exhibit or do not exhibit short-term synaptic depression—short-term depression produces phase-advances relative to nondepressing synapses. Short-term depression is modeled using two state-variables, a fast process with a time constant on the order of tens to hundreds of milliseconds, and a slow process with a time constant on the order of seconds to tens of seconds. These processes correspond to naturally occurring time constants observed at synapses that exhibit short-term depression. Inclusion of the fast process is sufficient for the generation of temporal disparities that are necessary for direction selectivity in the elementary Reichardt circuit. The addition of the slow process can enhance direction selectivity over time for stimuli that are sustained for periods of seconds or more. Transient (i.e., short-duration) stimuli do not evoke the slow process and therefore do not elicit enhanced direction selectivity. The addition of a sustained global, synchronous oscillation in the gamma frequency range can, however, drive the slow process and enhance direction selectivity to transient stimuli. This enhancement effect does not, however, occur for all combinations of model parameters. The ratio of depressing and nondepressing synapses determines the

  5. A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

    PubMed Central

    Honnuraiah, Suraj; Narayanan, Rishikesh

    2013-01-01

    Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles

  6. Altered synaptic plasticity in the mossy fibre pathway of transgenic mice expressing mutant amyloid precursor protein

    PubMed Central

    2010-01-01

    Aβ peptides derived from the cleavage of amyloid precursor protein are widely believed to play an important role in the pathophysiology of Alzheimer's disease. A common way to study the impact of these molecules on CNS function is to compare the physiology of transgenic mice that overproduce Aβ with non-transgenic animals. In the hippocampus, this approach has been frequently applied to the investigation of synaptic transmission and plasticity in the perforant and Schaffer collateral commissural pathways, the first and third components of the classical hippocampal trisynaptic circuit, respectively. Similar studies however have not been carried out on the remaining component of the trisynaptic circuit, the mossy fibre pathway. Using transverse hippocampal slices prepared from ~2 year old animals we have compared mossy fibre synaptic function in wild-type mice and their Tg2576 littermates which age-dependently overproduce Aβ. Input-output curves were not altered in slices from Tg2576 mice, but these animals exhibited a significant loss of the prominent frequency-facilitation expressed by the mossy fibre pathway. In addition to this change in short term synaptic plasticity, high frequency stimulation-induced, NMDA-receptor-independent LTP was absent in slices from the transgenic mice. These data represent the first description of functional deficits in the mossy fibre pathway of Aβ-overproducing transgenic mice. PMID:21040543

  7. Inhibitory Control of Synaptic and Behavioral Plasticity by Octopaminergic Signaling

    PubMed Central

    Koon, Alex C.; Budnik, Vivian

    2012-01-01

    Adrenergic receptors and their ligands are important regulators of synaptic plasticity and metaplasticity, but the exact mechanisms underlying their action are still poorly understood. Octopamine, the invertebrate homolog of mammalian adrenaline or noradrenaline, plays important roles in modulating behavior and synaptic functions. We previously uncovered an octopaminergic positive feedback mechanism to regulate structural synaptic plasticity during development and in response to starvation. Under this mechanism, activation of Octß2R autoreceptors by octopamine at octopaminergic neurons initiated a cAMP-dependent cascade that stimulated the development of new synaptic boutons at the Drosophila larval neuromuscular junction (NMJ). However, the regulatory mechanisms that served to brake such positive feedback were not known. Here, we report the presence of an alternative octopamine autoreceptor, Octß1R, with antagonistic functions on synaptic growth. Mutations in octß1r result in the overgrowth of both glutamatergic and octopaminergic NMJs suggesting that Octß1R is a negative regulator of synaptic expansion. As Octß2R, Octß1R functioned in a cell autonomous manner at presynaptic motorneurons. However, unlike Octß2R, which activated a cAMP pathway, Octß1R likely inhibited cAMP production through inhibitory Goα. Despite its inhibitory role, Octß1R was required for acute changes in synaptic structure in response to octopamine and for starvation-induced increase in locomotor speed. These results demonstrate the dual action of octopamine on synaptic growth and behavioral plasticity, and highlight the important role of inhibitory influences for normal responses to physiological stimuli. PMID:22553037

  8. Nanoconnectomic upper bound on the variability of synaptic plasticity

    PubMed Central

    Bartol, Thomas M; Bromer, Cailey; Kinney, Justin; Chirillo, Michael A; Bourne, Jennifer N; Harris, Kristen M; Sejnowski, Terrence J

    2015-01-01

    Information in a computer is quantified by the number of bits that can be stored and recovered. An important question about the brain is how much information can be stored at a synapse through synaptic plasticity, which depends on the history of probabilistic synaptic activity. The strong correlation between size and efficacy of a synapse allowed us to estimate the variability of synaptic plasticity. In an EM reconstruction of hippocampal neuropil we found single axons making two or more synaptic contacts onto the same dendrites, having shared histories of presynaptic and postsynaptic activity. The spine heads and neck diameters, but not neck lengths, of these pairs were nearly identical in size. We found that there is a minimum of 26 distinguishable synaptic strengths, corresponding to storing 4.7 bits of information at each synapse. Because of stochastic variability of synaptic activation the observed precision requires averaging activity over several minutes. DOI: http://dx.doi.org/10.7554/eLife.10778.001 PMID:26618907

  9. Cell-specific synaptic plasticity induced by network oscillations

    PubMed Central

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg RP

    2016-01-01

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. DOI: http://dx.doi.org/10.7554/eLife.14912.001 PMID:27218453

  10. Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules

    PubMed Central

    Sacramento, João; Wichert, Andreas; van Rossum, Mark C. W.

    2015-01-01

    It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L 1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817

  11. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity.

    PubMed

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  12. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

    PubMed Central

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  13. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

    PubMed Central

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated.

  14. Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity

    PubMed Central

    Liu, Ke; Lei, Run; Li, Qiong; Wang, Xin-Xin; Wu, Qian; An, Peng; Zhang, Jianchao; Zhu, Minyan; Xu, Zhiheng; Hong, Yang; Wang, Fudi; Shen, Ying; Li, Hongchang; Li, Huashun

    2016-01-01

    Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity. PMID:26880306

  15. Self-assembly and plasticity of synaptic domains through a reaction-diffusion mechanism.

    PubMed

    Haselwandter, Christoph A; Kardar, Mehran; Triller, Antoine; da Silveira, Rava Azeredo

    2015-09-01

    Signal transmission across chemical synapses relies crucially on neurotransmitter receptor molecules, concentrated in postsynaptic membrane domains along with scaffold and other postsynaptic molecules. The strength of the transmitted signal depends on the number of receptor molecules in postsynaptic domains, and activity-induced variation in the receptor number is one of the mechanisms of postsynaptic plasticity. Recent experiments have demonstrated that the reaction and diffusion properties of receptors and scaffolds at the membrane, alone, yield spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in neurons. On the basis of these experiments we develop a model describing synaptic receptor domains in terms of the underlying reaction-diffusion processes. Our model predicts that the spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in experiments depends on a few key reactions between receptors and scaffolds. Furthermore, our model suggests novel mechanisms for the alignment of pre- and postsynaptic domains and for short-term postsynaptic plasticity in receptor number. We predict that synaptic receptor domains localize in membrane regions with an increased receptor diffusion coefficient or a decreased scaffold diffusion coefficient. Similarly, we find that activity-dependent increases or decreases in receptor or scaffold diffusion yield a transient increase in the number of receptor molecules concentrated in postsynaptic domains. Thus, the proposed reaction-diffusion model puts forth a coherent set of biophysical mechanisms for the formation, stability, and plasticity of molecular domains on the postsynaptic membrane.

  16. Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus

    ERIC Educational Resources Information Center

    Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

    2008-01-01

    Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

  17. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    ERIC Educational Resources Information Center

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  18. ProBDNF negatively regulates neuronal remodeling, synaptic transmission and synaptic plasticity in hippocampus

    PubMed Central

    Yang, Jianmin; Harte-Hargrove, Lauren C.; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; LaFrancois, John J.; Bath, Kevin G.; Mark, Willie; Ballon, Douglas; Lee, Francis S.; Scharfman, Helen E.; Hempstead, Barbara L.

    2014-01-01

    Summary Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission and plasticity, effects that are distinct from mature BDNF. PMID:24746813

  19. The synaptic plasticity and memory hypothesis: encoding, storage and persistence

    PubMed Central

    Takeuchi, Tomonori; Duszkiewicz, Adrian J.; Morris, Richard G. M.

    2014-01-01

    The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain. PMID:24298167

  20. The synaptic plasticity and memory hypothesis: encoding, storage and persistence.

    PubMed

    Takeuchi, Tomonori; Duszkiewicz, Adrian J; Morris, Richard G M

    2014-01-01

    The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.

  1. Synaptic plasticity in cephalopods; more than just learning and memory?

    PubMed

    Brown, Euan R; Piscopo, Stefania

    2013-06-01

    The outstanding behavioural capacity of cephalopods is underpinned by a highly sophisticated nervous system anatomy and neural mechanisms that often differ significantly from similarly complex systems in vertebrates and insects. Cephalopods exhibit considerable behavioural flexibility and adaptability, and it might be expected that this should be supported by evident cellular and synaptic plasticity. Here, we review what little is known of the cellular mechanisms that underlie plasticity in cephalopods, particularly from the point of view of synaptic function. We conclude that cephalopods utilise short-, medium-, and long-term plasticity mechanisms that are superficially similar to those so far described in vertebrate and insect synapses. These mechanisms, however, often differ significantly from those in other animals at the biophysical level and are deployed not just in the central nervous system, but also to a limited extent in the peripheral nervous system and neuromuscular junctions.

  2. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo.

    PubMed

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, Christian

    2015-07-15

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (<12 μm) become depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT.

  3. Short-term Cortical Plasticity Associated With Feedback-Error Learning After Locomotor Training in a Patient With Incomplete Spinal Cord Injury

    PubMed Central

    Peters, Sue; Borich, Michael R.; Boyd, Lara A.; Lam, Tania

    2015-01-01

    Background and Purpose For rehabilitation strategies to be effective, training should be based on principles of motor learning, such as feedback-error learning, that facilitate adaptive processes in the nervous system by inducing errors and recalibration of sensory and motor systems. This case report suggests that locomotor resistance training can enhance somatosensory and corticospinal excitability and modulate resting-state brain functional connectivity in a patient with motor-incomplete spinal cord injury (SCI). Case Description The short-term cortical plasticity of a 31-year-old man who had sustained an incomplete SCI 9.5 years previously was explored in response to body-weight–supported treadmill training with velocity-dependent resistance applied with a robotic gait orthosis. The following neurophysiological and neuroimaging measures were recorded before and after training. Sensory evoked potentials were elicited by electrical stimulation of the tibial nerve and recorded from the somatosensory cortex. Motor evoked potentials were generated with transcranial magnetic stimulation applied over the tibialis anterior muscle representation in the primary motor cortex. Resting-state functional magnetic resonance imaging was performed to evaluate short-term changes in patterns of brain activity associated with locomotor training. Outcomes Somatosensory excitability and corticospinal excitability were observed to increase after locomotor resistance training. Motor evoked potentials increased (particularly at higher stimulation intensities), and seed-based resting-state functional magnetic resonance imaging analyses revealed increased functional connectivity strength in the motor cortex associated with the less affected side after training. Discussion The observations suggest evidence of short-term cortical plasticity in 3 complementary neurophysiological measures after one session of locomotor resistance training. Future investigation in a sample of people with

  4. Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

    PubMed Central

    Grønli, Janne; Soulé, Jonathan; Bramham, Clive R.

    2014-01-01

    Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function. PMID:24478645

  5. Translational regulatory mechanisms in persistent forms of synaptic plasticity.

    PubMed

    Kelleher, Raymond J; Govindarajan, Arvind; Tonegawa, Susumu

    2004-09-30

    Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role for neuronal activity-dependent mRNA translation, which may occur in dendrites for a subset of neuronal mRNAs. Recent work has begun to define the signaling mechanisms coupling synaptic activation to the protein synthesis machinery. The ERK and mTOR signaling pathways have been shown to regulate the activity of the general translational machinery, while the translation of particular classes of mRNAs is additionally controlled by gene-specific mechanisms. Rapid enhancement of the synthesis of a diverse array of neuronal proteins through such mechanisms provides the components necessary for persistent forms of LTP and LTD. These findings have important implications for the synapse specificity and associativity of protein synthesis-dependent changes in synaptic strength. PMID:15450160

  6. Synaptic Plasticity and Neurological Disorders in Neurotropic Viral Infections

    PubMed Central

    Atluri, Venkata Subba Rao; Hidalgo, Melissa; Samikkannu, Thangavel; Kurapati, Kesava Rao Venkata; Nair, Madhavan

    2015-01-01

    Based on the type of cells or tissues they tend to harbor or attack, many of the viruses are characterized. But, in case of neurotropic viruses, it is not possible to classify them based on their tropism because many of them are not primarily neurotropic. While rabies and poliovirus are considered as strictly neurotropic, other neurotropic viruses involve nervous tissue only secondarily. Since the AIDS pandemic, the interest in neurotropic viral infections has become essential for all clinical neurologists. Although these neurotropic viruses are able to be harbored in or infect the nervous system, not all the neurotropic viruses have been reported to cause disrupted synaptic plasticity and impaired cognitive functions. In this review, we have discussed the neurotropic viruses, which play a major role in altered synaptic plasticity and neurological disorders. PMID:26649202

  7. Synaptic plasticity in sleep: learning, homeostasis, and disease

    PubMed Central

    Wang, Gordon; Grone, Brian; Colas, Damien; Appelbaum, Lior; Mourrain, Philippe

    2012-01-01

    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence, and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer’s disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders. PMID:21840068

  8. Aging and Synaptic Plasticity: A Review

    PubMed Central

    Bergado, Jorge A.; Almaguer, William

    2002-01-01

    Aging affects all systems, but the brain seems to be particularly vulnerable to the action of negative, age-dependent factors. A gradual loss of memory functions is one of the earliest and most widespread consequences of brain aging. The causes for such impairment are still unclear. Long-term potentiation (LTP) is one form of neural plasticity, which has been proposed as the cellular correlate for memory. LTP is affected by aging, and such alteration might be causally related to memory dysfunction. In the present paper, we review the evidence sustaining the existence of a causal link between cognitive and LTP impairments, as well as the possible mechanisms involved. New results indicate a possible involvement of a deficient reinforcement of LTP by affective influences. PMID:12959152

  9. A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

    ERIC Educational Resources Information Center

    Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

    2005-01-01

    In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

  10. Convergent evidence for abnormal striatal synaptic plasticity in dystonia

    PubMed Central

    Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

    2010-01-01

    Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes

  11. Endocannabinoid-mediated synaptic plasticity and addiction-related behavior

    PubMed Central

    Sidhpura, Nimish; Parsons, Loren H.

    2011-01-01

    Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB1 receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression). PMID:21669214

  12. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    ERIC Educational Resources Information Center

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  13. A Nonlinear Cable Framework for Bidirectional Synaptic Plasticity

    PubMed Central

    Iannella, Nicolangelo; Launey, Thomas; Abbott, Derek; Tanaka, Shigeru

    2014-01-01

    Finding the rules underlying how axons of cortical neurons form neural circuits and modify their corresponding synaptic strength is the still subject of intense research. Experiments have shown that internal calcium concentration, and both the precise timing and temporal order of pre and postsynaptic action potentials, are important constituents governing whether the strength of a synapse located on the dendrite is increased or decreased. In particular, previous investigations focusing on spike timing-dependent plasticity (STDP) have typically observed an asymmetric temporal window governing changes in synaptic efficacy. Such a temporal window emphasizes that if a presynaptic spike, arriving at the synaptic terminal, precedes the generation of a postsynaptic action potential, then the synapse is potentiated; however if the temporal order is reversed, then depression occurs. Furthermore, recent experimental studies have now demonstrated that the temporal window also depends on the dendritic location of the synapse. Specifically, it was shown that in distal regions of the apical dendrite, the magnitude of potentiation was smaller and the window for depression was broader, when compared to observations from the proximal region of the dendrite. To date, the underlying mechanism(s) for such a distance-dependent effect is (are) currently unknown. Here, using the ionic cable theory framework in conjunction with the standard calcium based plasticity model, we show for the first time that such distance-dependent inhomogeneities in the temporal learning window for STDP can be largely explained by both the spatial and active properties of the dendrite. PMID:25148478

  14. ERK Pathway Activation Bidirectionally Affects Visual Recognition Memory and Synaptic Plasticity in the Perirhinal Cortex

    PubMed Central

    Silingardi, Davide; Angelucci, Andrea; De Pasquale, Roberto; Borsotti, Marco; Squitieri, Giovanni; Brambilla, Riccardo; Putignano, Elena; Pizzorusso, Tommaso; Berardi, Nicoletta

    2011-01-01

    ERK 1,2 pathway mediates experience-dependent gene transcription in neurons and several studies have identified its pivotal role in experience-dependent synaptic plasticity and in forms of long term memory involving hippocampus, amygdala, or striatum. The perirhinal cortex (PRHC) plays an essential role in familiarity-based object recognition memory. It is still unknown whether ERK activation in PRHC is necessary for recognition memory consolidation. Most important, it is unknown whether by modulating the gain of the ERK pathway it is possible to bidirectionally affect visual recognition memory and PRHC synaptic plasticity. We have first pharmacologically blocked ERK activation in the PRHC of adult mice and found that this was sufficient to impair long term recognition memory in a familiarity-based task, the object recognition task (ORT). We have then tested performance in the ORT in Ras-GRF1 knock-out (KO) mice, which exhibit a reduced activation of ERK by neuronal activity, and in ERK1 KO mice, which have an increased activation of ERK2 and exhibit enhanced striatal plasticity and striatal mediated memory. We found that Ras-GRF1 KO mice have normal short term memory but display a long term memory deficit; memory reconsolidation is also impaired. On the contrary, ERK1 KO mice exhibit a better performance than WT mice at 72 h retention interval, suggesting a longer lasting recognition memory. In parallel with behavioral data, LTD was strongly reduced and LTP was significantly smaller in PRHC slices from Ras-GRF1 KO than in WT mice while enhanced LTP and LTD were found in PRHC slices from ERK1 KO mice. PMID:22232579

  15. Information processing and synaptic plasticity at hippocampal mossy fiber terminals

    PubMed Central

    Evstratova, Alesya; Tóth, Katalin

    2014-01-01

    Granule cells of the dentate gyrus receive cortical information and they transform and transmit this code to the CA3 area via their axons, the mossy fibers (MFs). Structural and functional complexity of this network has been extensively studied at various organizational levels. This review is focused on the anatomical and physiological properties of the MF system. We will discuss the mechanism by which dentate granule cells process signals from single action potentials (APs), short bursts and longer stimuli. Various parameters of synaptic interactions at different target cells such as quantal transmission, short- and long-term plasticity (LTP) will be summarized. Different types of synaptic contacts formed by MFs have unique sets of rules for information processing during different rates of granule cell activity. We will investigate the complex interactions between key determinants of information transfer between the dentate gyrus and the CA3 area of the hippocampus. PMID:24550783

  16. Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus

    PubMed Central

    Calvo-Ochoa, Erika; Hernández-Ortega, Karina; Ferrera, Patricia; Morimoto, Sumiko; Arias, Clorinda

    2014-01-01

    Chronic consumption of high-fat-and-fructose diets (HFFD) is associated with the development of insulin resistance (InsRes) and obesity. Systemic insulin resistance resulting from long-term HFFD feeding has detrimental consequences on cognitive performance, neurogenesis, and long-term potentiation establishment, accompanied by neuronal alterations in the hippocampus. However, diet-induced hippocampal InsRes has not been reported. Therefore, we investigated whether short-term HFFD feeding produced hippocampal insulin signaling alterations associated with neuronal changes in the hippocampus. Rats were fed with a control diet or an HFFD consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water. Our results show that 7 days of HFFD feeding induce obesity and InsRes, associated with the following alterations in the hippocampus: (1) a decreased insulin signaling; (2) a decreased hippocampal weight; (3) a reduction in dendritic arborization in CA1 and microtubule-associated protein 2 (MAP-2) levels; (4) a decreased dendritic spine number in CA1 and synaptophysin content, along with an increase in tau phosphorylation; and finally, (5) an increase in reactive astrocyte associated with microglial changes. To our knowledge, this is the first report addressing hippocampal insulin signaling, as well as morphologic, structural, and functional modifications due to short-term HFFD feeding in the rat. PMID:24667917

  17. MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

    SciTech Connect

    Zhu Guoqi; Chen Ying; Huang Yuying; Li Qinglin; Behnisch, Thomas

    2011-08-01

    Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated f

  18. Synaptic competition in structural plasticity and cognitive function

    PubMed Central

    Ramiro-Cortés, Yazmín; Hobbiss, Anna F.; Israely, Inbal

    2014-01-01

    Connections between neurons can undergo long-lasting changes in synaptic strength correlating with changes in structure. These events require the synthesis of new proteins, the availability of which can lead to cooperative and competitive interactions between synapses for the expression of plasticity. These processes can occur over limited spatial distances and temporal periods, defining dendritic regions over which activity may be integrated and could lead to the physical rewiring of synapses into functional groups. Such clustering of inputs may increase the computational power of neurons by allowing information to be combined in a greater than additive manner. The availability of new proteins may be a key modulatory step towards activity-dependent, long-term growth or elimination of spines necessary for remodelling of connections. Thus, the aberrant growth or shrinkage of dendritic spines could occur if protein levels are misregulated. Indeed, such perturbations can be seen in several mental retardation disorders, wherein either too much or too little protein translation exists, matching an observed increase or decrease in spine density, respectively. Cellular events which alter protein availability could relieve a constraint on synaptic competition and disturb synaptic clustering mechanisms. These changes may be detrimental to modifications in neural circuitry following activity. PMID:24298158

  19. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    NASA Astrophysics Data System (ADS)

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-07-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

  20. Spike-driven synaptic plasticity: theory, simulation, VLSI implementation.

    PubMed

    Fusi, S; Annunziato, M; Badoni, D; Salamon, A; Amit, D J

    2000-10-01

    We present a model for spike-driven dynamics of a plastic synapse, suited for aVLSI implementation. The synaptic device behaves as a capacitor on short timescales and preserves the memory of two stable states (efficacies) on long timescales. The transitions (LTP/LTD) are stochastic because both the number and the distribution of neural spikes in any finite (stimulation) interval fluctuate, even at fixed pre- and postsynaptic spike rates. The dynamics of the single synapse is studied analytically by extending the solution to a classic problem in queuing theory (Takacs process). The model of the synapse is implemented in aVLSI and consists of only 18 transistors. It is also directly simulated. The simulations indicate that LTP/LTD probabilities versus rates are robust to fluctuations of the electronic parameters in a wide range of rates. The solutions for these probabilities are in very good agreement with both the simulations and measurements. Moreover, the probabilities are readily manipulable by variations of the chip's parameters, even in ranges where they are very small. The tests of the electronic device cover the range from spontaneous activity (3-4 Hz) to stimulus-driven rates (50 Hz). Low transition probabilities can be maintained in all ranges, even though the intrinsic time constants of the device are short (approximately 100 ms). Synaptic transitions are triggered by elevated presynaptic rates: for low presynaptic rates, there are essentially no transitions. The synaptic device can preserve its memory for years in the absence of stimulation. Stochasticity of learning is a result of the variability of interspike intervals; noise is a feature of the distributed dynamics of the network. The fact that the synapse is binary on long timescales solves the stability problem of synaptic efficacies in the absence of stimulation. Yet stochastic learning theory ensures that it does not affect the collective behavior of the network, if the transition probabilities are

  1. Presynaptic Active Zone Density during Development and Synaptic Plasticity.

    PubMed

    Clarke, Gwenaëlle L; Chen, Jie; Nishimune, Hiroshi

    2012-01-01

    Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density) during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs), the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS), active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  2. Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala.

    PubMed

    Monsey, Melissa S; Ota, Kristie T; Akingbade, Irene F; Hong, Ellie S; Schafe, Glenn E

    2011-01-01

    Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.

  3. Synaptic plasticity enables adaptive self-tuning critical networks.

    PubMed

    Stepp, Nigel; Plenz, Dietmar; Srinivasa, Narayan

    2015-01-01

    During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. PMID:25590427

  4. Synaptic Plasticity Enables Adaptive Self-Tuning Critical Networks

    PubMed Central

    Stepp, Nigel; Plenz, Dietmar; Srinivasa, Narayan

    2015-01-01

    During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. PMID:25590427

  5. Circuit Motifs for Contrast-Adaptive Differentiation in Early Sensory Systems: The Role of Presynaptic Inhibition and Short-Term Plasticity

    PubMed Central

    Zhang, Danke; Wu, Si; Rasch, Malte J.

    2015-01-01

    In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems. PMID:25723493

  6. Circuit motifs for contrast-adaptive differentiation in early sensory systems: the role of presynaptic inhibition and short-term plasticity.

    PubMed

    Zhang, Danke; Wu, Si; Rasch, Malte J

    2015-01-01

    In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems.

  7. Histone Deacetylase Inhibition Facilitates Massed Pattern-Induced Synaptic Plasticity and Memory

    ERIC Educational Resources Information Center

    Pandey, Kiran; Sharma, Kaushik P.; Sharma, Shiv K.

    2015-01-01

    Massed training is less effective for long-term memory formation than the spaced training. The role of acetylation in synaptic plasticity and memory is now well established. However, the role of this important protein modification in synaptic plasticity induced by massed pattern of stimulation or memory induced by massed training is not well…

  8. Reelin Supplementation Enhances Cognitive Ability, Synaptic Plasticity, and Dendritic Spine Density

    ERIC Educational Resources Information Center

    Rogers, Justin T.; Rusiana, Ian; Trotter, Justin; Zhao, Lisa; Donaldson, Erika; Pak, Daniel T.S.; Babus, Lenard W.; Peters, Melinda; Banko, Jessica L.; Chavis, Pascale; Rebeck, G. William; Hoe, Hyang-Sook; Weeber, Edwin J.

    2011-01-01

    Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive…

  9. Endocannabinoid system and synaptic plasticity: implications for emotional responses.

    PubMed

    Viveros, María-Paz; Marco, Eva-María; Llorente, Ricardo; López-Gallardo, Meritxell

    2007-01-01

    The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long-term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  10. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

    PubMed Central

    Viveros, María-Paz; Marco, Eva-María; Llorente, Ricardo; López-Gallardo, Meritxell

    2007-01-01

    The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long-term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms. PMID:17641734

  11. Synaptic plasticity and memory functions achieved in a WO3-x-based nanoionics device by using the principle of atomic switch operation.

    PubMed

    Yang, Rui; Terabe, Kazuya; Yao, Yiping; Tsuruoka, Tohru; Hasegawa, Tsuyoshi; Gimzewski, James K; Aono, Masakazu

    2013-09-27

    A compact neuromorphic nanodevice with inherent learning and memory properties emulating those of biological synapses is the key to developing artificial neural networks rivaling their biological counterparts. Experimental results showed that memorization with a wide time scale from volatile to permanent can be achieved in a WO3-x-based nanoionics device and can be precisely and cumulatively controlled by adjusting the device's resistance state and input pulse parameters such as the amplitude, interval, and number. This control is analogous to biological synaptic plasticity including short-term plasticity, long-term potentiation, transition from short-term memory to long-term memory, forgetting processes for short- and long-term memory, learning speed, and learning history. A compact WO3-x-based nanoionics device with a simple stacked layer structure should thus be a promising candidate for use as an inorganic synapse in artificial neural networks due to its striking resemblance to the biological synapse. PMID:23999098

  12. Synaptic plasticity and memory functions achieved in a WO3-x-based nanoionics device by using the principle of atomic switch operation

    NASA Astrophysics Data System (ADS)

    Yang, Rui; Terabe, Kazuya; Yao, Yiping; Tsuruoka, Tohru; Hasegawa, Tsuyoshi; Gimzewski, James K.; Aono, Masakazu

    2013-09-01

    A compact neuromorphic nanodevice with inherent learning and memory properties emulating those of biological synapses is the key to developing artificial neural networks rivaling their biological counterparts. Experimental results showed that memorization with a wide time scale from volatile to permanent can be achieved in a WO3-x-based nanoionics device and can be precisely and cumulatively controlled by adjusting the device’s resistance state and input pulse parameters such as the amplitude, interval, and number. This control is analogous to biological synaptic plasticity including short-term plasticity, long-term potentiation, transition from short-term memory to long-term memory, forgetting processes for short- and long-term memory, learning speed, and learning history. A compact WO3-x-based nanoionics device with a simple stacked layer structure should thus be a promising candidate for use as an inorganic synapse in artificial neural networks due to its striking resemblance to the biological synapse.

  13. Thrombin regulation of synaptic plasticity: implications for physiology and pathology.

    PubMed

    Maggio, Nicola; Itsekson, Zeev; Dominissini, Dan; Blatt, Ilan; Amariglio, Ninette; Rechavi, Gideon; Tanne, David; Chapman, Joab

    2013-09-01

    Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on long term potentiation (LTP) in mice hippocampal slices. Surprisingly, different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. High thrombin concentrations induced an NMDA dependent, slow onset LTP, whereas low concentrations of thrombin promoted a VGCCs, mGluR-5 dependent LTP through activated Protein C (aPC). Remarkably, aPC facilitated LTP by activating PAR1 through an Endothelial Protein C Receptor (EPCR)-mediated mechanism which involves intracellular calcium stores. These findings reveal a novel mechanism by which PAR1 may regulate the threshold for synaptic plasticity in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions.

  14. Role of phosphodiesterase 5 in synaptic plasticity and memory

    PubMed Central

    Puzzo, Daniela; Sapienza, Salvatore; Arancio, Ottavio; Palmeri, Agostino

    2008-01-01

    Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS). PMID:18728748

  15. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity

    PubMed Central

    Parekh, Puja K.; McClung, Colleen A.

    2016-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  16. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity.

    PubMed

    Parekh, Puja K; McClung, Colleen A

    2015-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  17. Spike-Timing–Dependent Synaptic Plasticity and Synaptic Democracy in Dendrites

    PubMed Central

    Gidon, Albert; Segev, Idan

    2009-01-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing–dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, gpeak, of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially “save” distal synapses from “dying out.” Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (gmax) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites. PMID:19357339

  18. Spike-timing-dependent synaptic plasticity and synaptic democracy in dendrites.

    PubMed

    Gidon, Albert; Segev, Idan

    2009-06-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing-dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, g(peak), of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially "save" distal synapses from "dying out." Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (g(max)) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites.

  19. Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity.

    PubMed

    Zeng, Menglong; Shang, Yuan; Araki, Yoichi; Guo, Tingfeng; Huganir, Richard L; Zhang, Mingjie

    2016-08-25

    Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD. PMID:27565345

  20. Spike-timing-dependent synaptic plasticity and synaptic democracy in dendrites.

    PubMed

    Gidon, Albert; Segev, Idan

    2009-06-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing-dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, g(peak), of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially "save" distal synapses from "dying out." Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (g(max)) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites. PMID:19357339

  1. Rapid change of AM fungal community in a rain-fed wheat field with short-term plastic film mulching practice.

    PubMed

    Liu, Yongjun; Mao, Lin; He, Xinhua; Cheng, Gang; Ma, Xiaojun; An, Lizhe; Feng, Huyuan

    2012-01-01

    Plastic film mulching (PFM) is a widely used agricultural practice in the temperate semi-arid Loess Plateau of China. However, how beneficial soil microbes, arbuscular mycorrhizal (AM) fungi in particular, respond to the PFM practice is not known. Here, a field experiment was performed to study the effects of a 3-month short-term PFM practice on AM fungi in plots planted with spring wheat (Triticum aestivum L. cv. Dingxi-2) in the Loess Plateau. AM colonization, spore density, wheat spike weight, and grain phosphorus (P) content were significantly increased in the PFM treatments, and these changes were mainly attributable to changes in soil properties such as available P and soil moisture. Alkaline phosphatase activity was significantly higher in PFM soils, but levels of AM fungal-related glomalin were similar between treatments. A total of nine AM fungal phylotypes were detected in root samples based on AM fungal SSU rDNA analyses, with six and five phylotypes in PFM and no-PFM plots, respectively. Although AM fungal phylotype richness was not statistically different between treatments, the community compositions were different, with four and three specific phylotypes in the PFM and no-PFM plots, respectively. A significant and rapid change in AM fungal, wheat, and soil variables following PFM suggested that the functioning of the AM symbiosis had been changed in the wheat field under PFM. Future studies are needed to investigate whether PFM applied over a longer term has a similar effect on the AM fungal community and their functioning in an agricultural ecosystem.

  2. LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB

    PubMed Central

    Todorovski, Zarko; Asrar, Suhail; Liu, Jackie; Saw, Ner Mu Nar; Joshi, Krutika; Cortez, Miguel A.; Snead, O. Carter; Xie, Wei

    2015-01-01

    Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1−/−) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1−/− mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor critical for LTM. Importantly, both L-LTP and LTM deficits in LIMK1−/− mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients with Williams syndrome through the enhancement of CREB activity in the adult brain. PMID:25645926

  3. LIMK1 regulates long-term memory and synaptic plasticity via the transcriptional factor CREB.

    PubMed

    Todorovski, Zarko; Asrar, Suhail; Liu, Jackie; Saw, Ner Mu Nar; Joshi, Krutika; Cortez, Miguel A; Snead, O Carter; Xie, Wei; Jia, Zhengping

    2015-04-01

    Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1(-/-)) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1(-/-) mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor critical for LTM. Importantly, both L-LTP and LTM deficits in LIMK1(-/-) mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients with Williams syndrome through the enhancement of CREB activity in the adult brain.

  4. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex

    PubMed Central

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G.; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H.; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-01-01

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep–wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans. PMID:27551934

  5. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex.

    PubMed

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-01-01

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep-wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans. PMID:27551934

  6. Abnormal cortical synaptic plasticity in minimal hepatic encephalopathy.

    PubMed

    Golaszewski, Stefan; Langthaler, Patrick B; Schwenker, Kerstin; Florea, Cristina; Christova, Monica; Brigo, Francesco; Trinka, Eugen; Nardone, Raffaele

    2016-07-01

    Minimal hepatic encephalopathy (MHE) represents the earliest stage of hepatic encephalopathy (HE). MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, while obvious clinical manifestations are lacking. In the present study, we aimed at assessing whether subjects with MHE showed alterations in synaptic plasticity within the motor cortex. Previous findings suggest that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. We employed therefore the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in the motor cortex of normal subjects. Fifteen patients with MHE and 15 age- and sex-matched cirrhotic patients without MHE were recruited. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min. In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude. On the contrary, in patients with MHE the MEP amplitude was slightly reduced after PAS. These findings demonstrated that associative sensorimotor plasticity, an indirect probe for motor learning, is impaired in MHE patients. PMID:27475415

  7. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance.

    PubMed

    Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G; Montecinos-Oliva, Carla; Arredondo, Sebastián B; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C

    2015-11-01

    Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders. PMID:26300486

  8. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance.

    PubMed

    Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G; Montecinos-Oliva, Carla; Arredondo, Sebastián B; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C

    2015-11-01

    Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders.

  9. The Role of GluK4 in Synaptic Plasticity and Affective Behavior in Mice

    NASA Astrophysics Data System (ADS)

    Catches, Justin Samuel

    Kainate receptors (KARs) are glutamate-gated ion channels that signal through both ionotropic and metabotropic pathways (Contractor et al., 2011). Combinations of five KAR subunits (GluK1-5) form tetrameric receptors with GluK1, GluK2, and GluK3 able to form functional homomeric channels. The high-affinity subunits, GluK4 and GluK5, do not form homomeric channels but modify the properties of heteromeric receptors. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs modulate synaptic plasticity. In this study, ablation of Grik4, which encodes GluK4, in mice reduced KAR synaptic currents and altered activation properties of postsynaptic receptors but left two forms of presynaptic short-term plasticity intact. Disruption of both Grik4 and Grik5 caused complete loss of the postsynaptic ionotropic KAR current and impaired presynaptic frequency facilitation. Additionally, KAR surface expression was altered at pre- and postsynaptic sites at the MF synapse. Despite the loss of ionotropic signaling, KAR-mediated inhibition of the slow afterhyperpolarization current, which is dependent on metabotropic signaling, was intact in CA3 neurons. Long-term potentiation at the MF-CA3 synapse was reduced, likely through a loss of KAR modulation of excitability of the presynaptic MF axons. Genetic variants in the human GRIK4 gene alter the susceptibility for affective disorders (Bloss and Hunter, 2010). We found that ablation of Grik4 in mice resulted in reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, and in two anxiogenic tests, marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim, a test of learned helplessness used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting

  10. ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity

    PubMed Central

    Robinson, J. E.; Paluch, J.; Dickman, D. K.; Joiner, W. J.

    2016-01-01

    It has been postulated that synaptic potentiation during waking is offset by a homoeostatic reduction in net synaptic strength during sleep. However, molecular mechanisms to support such a process are lacking. Here we demonstrate that deficiencies in the RNA-editing gene Adar increase sleep due to synaptic dysfunction in glutamatergic neurons in Drosophila. Specifically, the vesicular glutamate transporter is upregulated, leading to over-activation of NMDA receptors, and the reserve pool of glutamatergic synaptic vesicles is selectively expanded in Adar mutants. Collectively these changes lead to sustained neurotransmitter release under conditions that would otherwise result in synaptic depression. We propose that a shift in the balance from synaptic depression towards synaptic potentiation in sleep-promoting neurons underlies the increased sleep pressure of Adar-deficient animals. Our findings provide a plausible molecular mechanism linking sleep and synaptic plasticity. PMID:26813350

  11. ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity.

    PubMed

    Robinson, J E; Paluch, J; Dickman, D K; Joiner, W J

    2016-01-01

    It has been postulated that synaptic potentiation during waking is offset by a homoeostatic reduction in net synaptic strength during sleep. However, molecular mechanisms to support such a process are lacking. Here we demonstrate that deficiencies in the RNA-editing gene Adar increase sleep due to synaptic dysfunction in glutamatergic neurons in Drosophila. Specifically, the vesicular glutamate transporter is upregulated, leading to over-activation of NMDA receptors, and the reserve pool of glutamatergic synaptic vesicles is selectively expanded in Adar mutants. Collectively these changes lead to sustained neurotransmitter release under conditions that would otherwise result in synaptic depression. We propose that a shift in the balance from synaptic depression towards synaptic potentiation in sleep-promoting neurons underlies the increased sleep pressure of Adar-deficient animals. Our findings provide a plausible molecular mechanism linking sleep and synaptic plasticity.

  12. Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia

    PubMed Central

    Lepeta, Katarzyna; Kaczmarek, Leszek

    2015-01-01

    Recent findings implicate alterations in glutamate signaling, leading to aberrant synaptic plasticity, in schizophrenia. Matrix metalloproteinase-9 (MMP-9) has been shown to regulate glutamate receptors, be regulated by glutamate at excitatory synapses, and modulate physiological and morphological synaptic plasticity. By means of functional gene polymorphism, gene responsiveness to antipsychotics and blood plasma levels MMP-9 has recently been implicated in schizophrenia. This commentary critically reviews these findings based on the hypothesis that MMP-9 contributes to pathological synaptic plasticity in schizophrenia. PMID:25837304

  13. Myosin II regulates actin rearrangement-related structural synaptic plasticity during conditioned taste aversion memory extinction.

    PubMed

    Bi, Ai-Ling; Wang, Yue; Zhang, Shuang; Li, Bo-Qin; Sun, Zong-Peng; Bi, Hong-Sheng; Chen, Zhe-Yu

    2015-03-01

    Similar to memory formation, memory extinction is also a new learning process that requires synaptic plasticity. Actin rearrangement is fundamental for synaptic plasticity, however, whether actin rearrangement in the infralimbic cortex (IL) plays a role in memory extinction, as well as the mechanisms underlying it, remains unclear. Here, using a conditioned taste aversion (CTA) paradigm, we demonstrated increased synaptic density and actin rearrangement in the IL during the extinction of CTA. Targeted infusion of an actin rearrangement inhibitor, cytochalasin D, into the IL impaired memory extinction and de novo synapse formation. Notably, we also found increased myosin II phosphorylation in the IL during the extinction of CTA. Microinfusion of a specific inhibitor of the myosin II ATPase, blebbistatin (Blebb), into the IL impaired memory extinction as well as the related actin rearrangement and changes in synaptic density. Moreover, the extinction deficit and the reduction of synaptic density induced by Blebb could be rescued by the actin polymerization stabilizer jasplakinolide (Jasp), suggesting that myosin II acts via actin filament polymerization to stabilize synaptic plasticity during the extinction of CTA. Taken together, we conclude that myosin II may regulate the plasticity of actin-related synaptic structure during memory extinction. Our studies provide a molecular mechanism for understanding the plasticity of actin rearrangement-associated synaptic structure during memory extinction.

  14. Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

    PubMed

    Wieland, Sebastian; Schindler, Sebastian; Huber, Cathrin; Köhr, Georg; Oswald, Manfred J; Kelsch, Wolfgang

    2015-07-01

    Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of <1 s. Compatible with predictions of dynamic value assignment, the synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum.

  15. Cross-talk induces bifurcations in nonlinear models of synaptic plasticity.

    PubMed

    Elliott, Terry

    2012-02-01

    Linear models of synaptic plasticity provide a useful starting-point for examining the dynamics of neuronal development and learning, but their inherent problems are well known. Models of synaptic plasticity that embrace the demands of biological realism are therefore typically nonlinear. Viewed from a more abstract perspective, nonlinear models of synaptic plasticity are a subset of nonlinear dynamical systems. As such, they may therefore exhibit bifurcations under the variation of control parameters, including noise and errors in synaptic updates. One source of noise or error is the cross-talk that occurs during otherwise Hebbian plasticity. Under cross-talk, stimulation of a set of synapses can induce or modify plasticity in adjacent, unstimulated synapses. Here, we analyze two nonlinear models of developmental synaptic plasticity and a model of independent component analysis in the presence of a simple model of cross-talk. We show that cross-talk does indeed induce bifurcations in these models, entirely destroying their ability to acquire either developmentally or learning-related patterns of fixed points. Importantly, the critical level of cross-talk required to induce bifurcations in these models is very sensitive to the statistics of the afferents' activities and the number of afferents synapsing on a postsynaptic cell. In particular, the critical level can be made arbitrarily small. Because bifurcations are inevitable in nonlinear models, our results likely apply to many nonlinear models of synaptic plasticity, although the precise details vary by model. Hence, many nonlinear models of synaptic plasticity are potentially fatally compromised by the toxic influence of cross-talk and other sources of noise and errors more generally. We conclude by arguing that biologically realistic models of synaptic plasticity must be robust against noise-induced bifurcations and that biological systems may have evolved strategies to circumvent their possible dangers.

  16. Studying synaptic plasticity in the human brain and opportunities for drug discovery.

    PubMed

    Nathan, Pradeep J; Cobb, Stuart R; Lu, Bai; Bullmore, Edward T; Davies, Ceri H

    2011-10-01

    Synaptic plasticity is the ability of synaptic connections between neurons to be strengthened or weakened; a process that is central to the information processing within the brain and which plays a particularly important role in enabling higher cognitive processes [1,2]. Its role in disease is becoming increasingly clear across a wide spectrum of CNS disorders. Thus, for example, dysfunctional synaptic plasticity has been reported in neurodegenerative disorders such as Alzheimer's Disease (AD) as well as in schizophrenia and in a range of disorders associated with learning disabilities [3]. Moreover, maladaptive plasticity processes in response to specific external challenges are believed to underlie disorders such as addiction and post-traumatic stress disorder (PTSD). The molecular basis of normal and disease plasticity is rapidly being unravelled such that synaptic plasticity now provides a unique platform from which to launch the hunt for highly innovative drugs to treat CNS disease by either, firstly, rectifying identifiable abnormalities in these processes, or secondly, utilizing these processes as a vehicle to rectify, or bypass, other mechanisms underlying disease. In this respect, recent advances have been made in studying synaptic plasticity in humans at the molecular through to clinical level and these approaches now provide a real opportunity to test synaptic plasticity as a treatment paradigm for a wide variety of CNS disorders.

  17. Synchrony arising from a balanced synaptic plasticity in a network of heterogeneous neural oscillators.

    PubMed

    Karbowski, Jan; Ermentrout, G Bard

    2002-03-01

    We investigate the dynamics of a recurrent network of coupled heterogeneous neural oscillators with experimentally observed spike-timing-dependent synaptic plasticity. We show both theoretically and by computer simulations that, in a regime of a balance between synaptic potentiation and depression, the network of such oscillators converges to a stable synchronous state. The stability of this state is fostered by flexible synaptic weights which adjust themselves based on the relative timing of firing of pre- and postsynaptic oscillators.

  18. Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity.

    PubMed

    Cho, Richard W; Buhl, Lauren K; Volfson, Dina; Tran, Adrienne; Li, Feng; Akbergenova, Yulia; Littleton, J Troy

    2015-11-18

    Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca(2+) entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity.

  19. The Formation of Multi-synaptic Connections by the Interaction of Synaptic and Structural Plasticity and Their Functional Consequences

    PubMed Central

    Fauth, Michael; Wörgötter, Florentin; Tetzlaff, Christian

    2015-01-01

    Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical layers. All of these distributions are bimodal with one peak at zero and a second one at a small number (3–8) of synapses. In this study, using a probabilistic model of structural plasticity, which depends on the synaptic weights, we explore how these distributions can emerge and which functional consequences they have. We find that bimodal distributions arise generically from the interaction of structural plasticity with synaptic plasticity rules that fulfill the following biological realistic constraints: First, the synaptic weights have to grow with the postsynaptic activity. Second, this growth curve and/or the input-output relation of the postsynaptic neuron have to change sub-linearly (negative curvature). As most neurons show such input-output-relations, these constraints can be fulfilled by many biological reasonable systems. Given such a system, we show that the different activities, which can explain the layer-specific distributions, correspond to experimentally observed activities. Considering these activities as working point of the system and varying the pre- or postsynaptic stimulation reveals a hysteresis in the number of synapses. As a consequence of this, the connectivity between two neurons can be controlled by activity but is also safeguarded against overly fast changes. These results indicate that the complex dynamics between activity and plasticity will, already between a pair of neurons, induce a variety of possible stable synaptic distributions, which could support memory mechanisms. PMID:25590330

  20. Can short-term oral fine motor training affect precision of task performance and induce cortical plasticity of the jaw muscles?

    PubMed

    Zhang, Hong; Kumar, Abhishek; Kothari, Mohit; Luo, Xiaoping; Trulsson, Mats; Svensson, Krister G; Svensson, Peter

    2016-07-01

    The aim was to test the hypothesis that short-term oral sensorimotor training of the jaw muscles would increase the precision of task performance and induce neuroplastic changes in the corticomotor pathways, related to the masseter muscle. Fifteen healthy volunteers performed six series with ten trials of an oral sensorimotor task. The task was to manipulate and position a spherical chocolate candy in between the anterior teeth and split it into two equal halves. The precision of the task performance was evaluated by comparing the ratio between the two split halves. A series of "hold-and-split" tasks was also performed before and after the training. The hold force and split force along with the electromyographic (EMG) activity of jaw muscles were recorded. Motor-evoked potentials and cortical motor maps of the right masseter muscle were evoked by transcranial magnetic stimulation. There was a significant effect of series on the precision of the task performance during the short-term oral sensorimotor training (P < 0.002). The hold force during the "hold-and-split" task was significantly lower after training than before the short-term training (P = 0.011). However, there was no change in the split force and the EMG activity of the jaw muscles before and after the training. Further, there was a significant increase in the amplitude of the motor-evoked potentials (P < 0.016) and in the motor cortex map areas (P = 0.033), after the short-term oral sensorimotor training. Therefore, short-term oral sensorimotor task training increased the precision of task performance and induced signs of neuroplastic changes in the corticomotor pathways, related to the masseter muscle.

  1. Can short-term oral fine motor training affect precision of task performance and induce cortical plasticity of the jaw muscles?

    PubMed

    Zhang, Hong; Kumar, Abhishek; Kothari, Mohit; Luo, Xiaoping; Trulsson, Mats; Svensson, Krister G; Svensson, Peter

    2016-07-01

    The aim was to test the hypothesis that short-term oral sensorimotor training of the jaw muscles would increase the precision of task performance and induce neuroplastic changes in the corticomotor pathways, related to the masseter muscle. Fifteen healthy volunteers performed six series with ten trials of an oral sensorimotor task. The task was to manipulate and position a spherical chocolate candy in between the anterior teeth and split it into two equal halves. The precision of the task performance was evaluated by comparing the ratio between the two split halves. A series of "hold-and-split" tasks was also performed before and after the training. The hold force and split force along with the electromyographic (EMG) activity of jaw muscles were recorded. Motor-evoked potentials and cortical motor maps of the right masseter muscle were evoked by transcranial magnetic stimulation. There was a significant effect of series on the precision of the task performance during the short-term oral sensorimotor training (P < 0.002). The hold force during the "hold-and-split" task was significantly lower after training than before the short-term training (P = 0.011). However, there was no change in the split force and the EMG activity of the jaw muscles before and after the training. Further, there was a significant increase in the amplitude of the motor-evoked potentials (P < 0.016) and in the motor cortex map areas (P = 0.033), after the short-term oral sensorimotor training. Therefore, short-term oral sensorimotor task training increased the precision of task performance and induced signs of neuroplastic changes in the corticomotor pathways, related to the masseter muscle. PMID:26914481

  2. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

    PubMed

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-05-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  3. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

    PubMed Central

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-01-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  4. Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity

    PubMed Central

    Maag, Jesper L. V.; Panja, Debabrata; Sporild, Ida; Patil, Sudarshan; Kaczorowski, Dominik C.; Bramham, Clive R.; Dinger, Marcel E.; Wibrand, Karin

    2015-01-01

    Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders. PMID:26483626

  5. Area-Specific Alterations of Synaptic Plasticity in the 5XFAD Mouse Model of Alzheimer’s Disease: Dissociation between Somatosensory Cortex and Hippocampus

    PubMed Central

    Crouzin, Nadine; Baranger, Kevin; Cavalier, Mélanie; Marchalant, Yannick; Cohen-Solal, Catherine; Roman, François S.; Khrestchatisky, Michel; Rivera, Santiago; Féron, François; Vignes, Michel

    2013-01-01

    Transgenic mouse models of Alzheimer’s disease (AD) that overproduce the amyloid beta peptide (Aβ) have highlighted impairments of hippocampal long-term synaptic plasticity associated with the progression of the disease. Here we examined whether the characteristics of one of the hallmarks of AD, i.e. Aβ deposition, in both the somatosensory cortex and the hippocampus, correlated with specific losses of synaptic plasticity in these areas. For this, we evaluated the occurrence of long-term potentiation (LTP) in the cortex and the hippocampus of 6-month old 5xFAD transgenic mice that exhibited massive Aβ deposition in both regions but with different features: in cortical areas a majority of Aβ deposits comprised a dense core surrounded by a diffuse corona while such kind of Aβ deposition was less frequently observed in the hippocampus. In order to simultaneously monitor synaptic changes in both areas, we developed a method based on the use of Multi-Electrode Arrays (MEA). When compared with wild-type (WT) mice, basal transmission was significantly reduced in both areas in 5xFAD mice, while short-term synaptic plasticity was unaffected. The induction of long-term changes of synaptic transmission by different protocols revealed that in 5xFAD mice, LTP in the layer 5 of the somatosensory cortex was more severely impaired than LTP triggered in the CA1 area of the hippocampus. We conclude that cortical plasticity is deficient in the 5xFAD model and that this deficit could be correlated with the proportion of diffuse plaques in 5xFAD mice. PMID:24069328

  6. Synaptic plasticity defect following visual deprivation in Alzheimer disease model transgenic mice

    PubMed Central

    William, Christopher M.; Andermann, Mark L.; Goldey, Glenn J.; Roumis, Demetris K.; Reid, R. Clay; Shatz, Carla J.; Albers, Mark W.; Frosch, Matthew P.; Hyman, Bradley T.

    2012-01-01

    Amyloid-beta (Aβ)-induced changes in synaptic function in experimental models of Alzheimer disease (AD) suggest that Aβ generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of amyloid precursor protein (APP) overexpression on a well-characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity (ODP). Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aβ overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aβ exposure contributes to cognitive impairment in AD. PMID:22674275

  7. Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall

    PubMed Central

    Kim, Il Hwan; Wang, Hong; Soderling, Scott H; Yasuda, Ryohei

    2014-01-01

    Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report that postnatal forebrain deletion of Cdc42 leads to deficits in synaptic plasticity and in remote memory recall using conditional knockout of Cdc42. We found that deletion of Cdc42 impaired LTP in the Schaffer collateral synapses and postsynaptic structural plasticity of dendritic spines in CA1 pyramidal neurons in the hippocampus. Additionally, loss of Cdc42 did not affect memory acquisition, but instead significantly impaired remote memory recall. Together these results indicate that the postnatal functions of Cdc42 may be crucial for the synaptic plasticity in hippocampal neurons, which contribute to the capacity for remote memory recall. DOI: http://dx.doi.org/10.7554/eLife.02839.001 PMID:25006034

  8. Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

    PubMed Central

    Bonansco, Christian; Fuenzalida, Marco

    2016-01-01

    Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks. PMID:27006834

  9. Diverse synaptic plasticity mechanisms orchestrated to form and retrieve memories in spiking neural networks

    PubMed Central

    Zenke, Friedemann; Agnes, Everton J.; Gerstner, Wulfram

    2015-01-01

    Synaptic plasticity, the putative basis of learning and memory formation, manifests in various forms and across different timescales. Here we show that the interaction of Hebbian homosynaptic plasticity with rapid non-Hebbian heterosynaptic plasticity is, when complemented with slower homeostatic changes and consolidation, sufficient for assembly formation and memory recall in a spiking recurrent network model of excitatory and inhibitory neurons. In the model, assemblies were formed during repeated sensory stimulation and characterized by strong recurrent excitatory connections. Even days after formation, and despite ongoing network activity and synaptic plasticity, memories could be recalled through selective delay activity following the brief stimulation of a subset of assembly neurons. Blocking any component of plasticity prevented stable functioning as a memory network. Our modelling results suggest that the diversity of plasticity phenomena in the brain is orchestrated towards achieving common functional goals. PMID:25897632

  10. Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

    ERIC Educational Resources Information Center

    Lombroso, Paul; Ogren, Marilee

    2009-01-01

    The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

  11. Spike train auto-structure impacts post-synaptic firing and timing-based plasticity.

    PubMed

    Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

    2011-01-01

    Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

  12. Age-related impairments in neuronal plasticity markers and astrocytic GFAP and their reversal by late-onset short term dietary restriction.

    PubMed

    Kaur, Manpreet; Sharma, Sandeep; Kaur, Gurcharan

    2008-12-01

    Recent studies on the effects of dietary restriction (DR) in rodents and primates have shown that even late-onset short-term regimens can bring about comparable beneficial changes seen in animals subjected to life-long DR. We studied the effect of aging on the expression of neural cell adhesion molecule (NCAM), its polysialylated form PSA-NCAM and astrocytic marker glial fibrillary acidic protein (GFAP) by immunohistofluorescent staining and immunoblotting in 1, 3, 6, 18 and 24 months old male wistar rats. Maximum expression of NCAM and PSA-NCAM was observed in sub-granular zone (SGZ) or granular cell layer (GCL) of hippocampus, arcuate region and paraventricular area of hypothalamus and piriform cortex layer II from 1 and 3 months old rats, thereafter, gradual downregulation was observed in 6, 18 and 24 months old rats. Progressive increase in astrocytic GFAP expression was noticed in these regions of brain with age. We further addressed whether DR initiated in late adulthood in 24 months old rats confers beneficial effects and can reverse changes in expression of NCAM, PSA-NCAM and GFAP. These results suggest that even late-onset short term DR regimen in old rats can have beneficial effects on neuroplasticity.

  13. Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice.

    PubMed

    Szinyei, Csaba; Narayanan, Rajeevan T; Pape, Hans-Christian

    2007-02-01

    After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear-related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear-conditioned, pseudo-trained and naïve adult mice. Theta-burst tetanization of thalamic afferent inputs to the LA evoked an input-specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 microM), an antagonist of Ca2+-permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA(B) receptor antagonist (CGP 55845A, 10 microM) or an NMDA receptor antagonist (APV, 50 microM), or intracellular application of BAPTA (10 mM), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo-conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear-memory acquisition or consolidation.

  14. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot.

    PubMed

    Grinke, Eduard; Tetzlaff, Christian; Wörgötter, Florentin; Manoonpong, Poramate

    2015-01-01

    Walking animals, like insects, with little neural computing can effectively perform complex behaviors. For example, they can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a many degrees-of-freedom (DOFs) walking robot is a challenging task. Thus, in this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking robot. The turning information is transmitted as descending steering signals to the neural locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations. The adaptation also enables the robot to effectively escape from sharp corners or deadlocks. Using backbone joint control embedded in the the locomotion control allows the robot to climb over small obstacles

  15. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot.

    PubMed

    Grinke, Eduard; Tetzlaff, Christian; Wörgötter, Florentin; Manoonpong, Poramate

    2015-01-01

    Walking animals, like insects, with little neural computing can effectively perform complex behaviors. For example, they can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a many degrees-of-freedom (DOFs) walking robot is a challenging task. Thus, in this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking robot. The turning information is transmitted as descending steering signals to the neural locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations. The adaptation also enables the robot to effectively escape from sharp corners or deadlocks. Using backbone joint control embedded in the the locomotion control allows the robot to climb over small obstacles

  16. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot

    PubMed Central

    Grinke, Eduard; Tetzlaff, Christian; Wörgötter, Florentin; Manoonpong, Poramate

    2015-01-01

    Walking animals, like insects, with little neural computing can effectively perform complex behaviors. For example, they can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a many degrees-of-freedom (DOFs) walking robot is a challenging task. Thus, in this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking robot. The turning information is transmitted as descending steering signals to the neural locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations. The adaptation also enables the robot to effectively escape from sharp corners or deadlocks. Using backbone joint control embedded in the the locomotion control allows the robot to climb over small obstacles

  17. Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity.

    PubMed

    Arendt, Thomas; Brückner, Martina K

    2007-04-01

    Higher cerebral functions are based upon a dynamic organization of neuronal networks. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. In other words, synaptic plasticity can only occur on the expense of the ability to proliferate. Previously, we have put forward a hypothesis, coined "Dr. Jekyll and Mr. Hyde concept" that differentiated neurons after having withdrawn from the cell cycle are able to use those molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity [T. Arendt, Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways The Dr. Jekyll and Mr. Hyde Theory of Alzheimer's disease or The yin and yang of Neuroplasticity. Progr. Neurobiol. 71 (2003) 83-248]. The existence of these alternative effector pathways within a neuron might put it on the risk to erroneously convert signals derived from plastic synaptic changes into cell cycle activation which subsequently leads to cell death. Here we add further evidence to this hypothesis demonstrating a tight association of the origin recognition complex (ORC) with neurofibrillar pathology in AD. The ORC is a critical "guard" of DNA replication and point of convergence of numerous functionally redundant signaling pathways involved in cell cycle progression and transcriptional silencing of apoptotic programmes. ORC subunits in the mammalian brain and their homologes in Drosophila, however, have further been implicated in the regulation of structural neuronal plasticity and cognitive function. We propose that the abnormal subcellular distribution and segregation of ORC proteins in AD might compromise their physiological function in gene silencing and plasticity. This might result in cell cycle activation, DNA-replication and de-repression of apoptotic programmes. ORC subunits might, thus, provide a direct molecular

  18. A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission

    PubMed Central

    Ouanounou, Gilles; Baux, Gérard; Bal, Thierry

    2016-01-01

    Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability. DOI: http://dx.doi.org/10.7554/eLife.12190.001 PMID:27138195

  19. Conformational signaling required for synaptic plasticity by the NMDA receptor complex.

    PubMed

    Aow, Jonathan; Dore, Kim; Malinow, Roberto

    2015-11-24

    The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.

  20. Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics

    PubMed Central

    Rust, Marco B; Gurniak, Christine B; Renner, Marianne; Vara, Hugo; Morando, Laura; Görlich, Andreas; Sassoè-Pognetto, Marco; Banchaabouchi, Mumna Al; Giustetto, Maurizio; Triller, Antoine; Choquet, Daniel; Witke, Walter

    2010-01-01

    Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin-binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n-cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long-term potentiation and long-term depression. Loss of n-cofilin-mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n-cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability. PMID:20407421

  1. Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease

    PubMed Central

    Balietti, Marta; Tamagnini, Francesco; Fattoretti, Patrizia; Burattini, Costanza; Casoli, Tiziana; Platano, Daniela; Lattanzio, Fabrizia

    2012-01-01

    Abstract Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here. PMID:22533439

  2. Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

    PubMed Central

    Jakovcevski, Mira; Ruan, Hongyu; Shen, Erica Y.; Dincer, Aslihan; Javidfar, Behnam; Ma, Qi; Peter, Cyril J.; Cheung, Iris; Mitchell, Amanda C.; Jiang, Yan; Lin, Cong L.; Pothula, Venu; Stewart, A. Francis; Ernst, Patricia

    2015-01-01

    Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion. PMID:25834037

  3. Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.

    PubMed

    Jakovcevski, Mira; Ruan, Hongyu; Shen, Erica Y; Dincer, Aslihan; Javidfar, Behnam; Ma, Qi; Peter, Cyril J; Cheung, Iris; Mitchell, Amanda C; Jiang, Yan; Lin, Cong L; Pothula, Venu; Stewart, A Francis; Ernst, Patricia; Yao, Wei-Dong; Akbarian, Schahram

    2015-04-01

    Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion. PMID:25834037

  4. Learning structure of sensory inputs with synaptic plasticity leads to interference

    PubMed Central

    Chrol-Cannon, Joseph; Jin, Yaochu

    2015-01-01

    Synaptic plasticity is often explored as a form of unsupervised adaptation in cortical microcircuits to learn the structure of complex sensory inputs and thereby improve performance of classification and prediction. The question of whether the specific structure of the input patterns is encoded in the structure of neural networks has been largely neglected. Existing studies that have analyzed input-specific structural adaptation have used simplified, synthetic inputs in contrast to complex and noisy patterns found in real-world sensory data. In this work, input-specific structural changes are analyzed for three empirically derived models of plasticity applied to three temporal sensory classification tasks that include complex, real-world visual and auditory data. Two forms of spike-timing dependent plasticity (STDP) and the Bienenstock-Cooper-Munro (BCM) plasticity rule are used to adapt the recurrent network structure during the training process before performance is tested on the pattern recognition tasks. It is shown that synaptic adaptation is highly sensitive to specific classes of input pattern. However, plasticity does not improve the performance on sensory pattern recognition tasks, partly due to synaptic interference between consecutively presented input samples. The changes in synaptic strength produced by one stimulus are reversed by the presentation of another, thus largely preventing input-specific synaptic changes from being retained in the structure of the network. To solve the problem of interference, we suggest that models of plasticity be extended to restrict neural activity and synaptic modification to a subset of the neural circuit, which is increasingly found to be the case in experimental neuroscience. PMID:26300769

  5. All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

    PubMed

    Vivar, Carmen; Potter, Michelle C; van Praag, Henriette

    2013-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

  6. All About Running: Synaptic Plasticity, Growth Factors and Adult Hippocampal Neurogenesis

    PubMed Central

    Vivar, Carmen; Potter, Michelle C.; van Praag, Henriette

    2015-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF). PMID:22847651

  7. Fear Extinction as a Model for Synaptic Plasticity in Major Depressive Disorder

    PubMed Central

    Feige, Bernd; Blechert, Jens; Normann, Claus; Nissen, Christoph

    2014-01-01

    Background The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls. Methods Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter. Results After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration. Conclusions The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder. PMID:25545818

  8. The effect of short-term exposure to energy-matched diets enriched in fat or sugar on memory, gut microbiota and markers of brain inflammation and plasticity.

    PubMed

    Beilharz, Jessica E; Kaakoush, Nadeem O; Maniam, Jayanthi; Morris, Margaret J

    2016-10-01

    Short-term exposure to high-energy diets impairs memory but there is little data on the relative contributions of fat and sugar to these deficits or the mechanisms responsible. Here, we investigated how these different macronutrients affect memory, neuroinflammation and neuroplasticity markers and the gut microbiota. Rats were fed matched purified diets for 2weeks; Control, Sugar, Saturated Fatty Acid (SFA) or Polyunsaturated Fatty Acid (PUFA), which varied only in the percentage of energy available from sugar and the amount and type of fat. Rats consuming SFA and Sugar were impaired on hippocampal-dependent place recognition memory compared to Controls and PUFA rats, despite all rats consuming similar amounts of energy. All rats performed comparably on the object recognition task. Hippocampal and hypothalamic inflammatory markers were not substantially affected by the diets and there was no change in the neuroplasticity marker, brain-derived neurotrophic factor. Each of the diets significantly altered the microbial composition in distinct ways. Specifically, the relative abundance of 89 taxa differed significantly between groups with the majority of these changes accounted for by the Clostridiales order and within that, Lachnospiraceae and Ruminococcaceae. These taxa showed a range of macronutrient specific correlations with place memory. In addition, Distance based Linear Models found relationships between memory, inflammation-related hippocampal genes and the gut microbiota. In conclusion, our study shows that the macronutrient profile of the diet is crucial for diet-induced memory deficits and suggests a possible link between diet, the gut microbiota and hippocampal inflammatory genes.

  9. A spaceflight study of synaptic plasticity in adult rat vestibular maculas

    NASA Technical Reports Server (NTRS)

    Ross, M. D.

    1994-01-01

    Behavioral signs of vestibular perturbation in altered gravity have not been well correlated with structural modifications in neurovestibular centers. This ultrastructural research investigated synaptic plasticity in hair cells of adult rat utricular maculas exposed to microgravity for nine days on a space shuttle. The hypothesis was that synaptic plasticity would be more evident in type II hair cells because they are part of a distributed modifying macular circuitry. All rats were shared with other investigators and were subjected to treatments unrelated to this experiment. Maculas were obtained from flight and control rats after shuttle return (R + 0) and nine days post-flight (R + 9). R + 9 rats had chromodacryorrhea, a sign of acute stress. Tissues were prepared for ultrastructural study by conventional methods. Ribbon synapses were counted in fifty serial sections from medial utricular macular regions of three rats of each flight and control group. Counts in fifty additional consecutive sections from one sample in each group established method reliability. All synapses were photographed and located to specific cells on mosaics of entire sections. Pooled data were analyzed statistically. Flown rats showed abnormal posture and movement at R + 0. They had statistically significant increases in total ribbon synapses and in sphere-like ribbons in both kinds of hair cells; in type II cells, pairs of synapses nearly doubled and clusters of 3 to 6 synapses increased twelve-fold. At R + 9, behavioral signs were normal. However, synapse counts remained high in both kinds of hair cells of flight maculas and were elevated in control type II cells. Only counts in type I cells showed statistically significant differences at R + 9. High synaptic counts at R + 9 may have resulted from stress due to experimental treatments. The results nevertheless demonstrate that adult maculas retain the potential for synaptic plasticity. Type II cells exhibited more synaptic plasticity, but

  10. ERK, synaptic plasticity and acid-induced muscle pain

    PubMed Central

    Yang, Hsiu-Wen; Yen, Chen-Tung; Chen, Chien-Chang; Chen, Chih-Cheng; Cheng, Sin-Jhong

    2011-01-01

    Chronic pain is characterized by post-injury pain hypersensitivity. Current evidence suggests that it might result from altered neuronal excitability and/or synaptic functions in pain-related pathways and brain areas, an effect known as central sensitization. Increased activity of extracellular signal-regulated kinase (ERK) has been well-demonstrated in the dorsal horn of the spinal cord in chronic pain animal models. Recently, increased ERK activity has also been identified in two supraspinal areas, the central amygdala and the paraventricular thalamic nucleus anterior. Our recent work on the capsular central amygdala has shown that this increased ERK activity can enhance synaptic transmission, which might account for central sensitization and behavior hypersensitivity in animals receiving noxious stimuli. PMID:21966555

  11. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

    PubMed Central

    Oliva, Carolina A.; Vargas, Jessica Y.; Inestrosa, Nibaldo C.

    2013-01-01

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID:24348327

  12. The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory

    PubMed Central

    Marciniak, Elodie; Faivre, Emilie; Dutar, Patrick; Alves Pires, Claire; Demeyer, Dominique; Caillierez, Raphaëlle; Laloux, Charlotte; Buée, Luc; Blum, David; Humez, Sandrine

    2015-01-01

    Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions. PMID:26511387

  13. Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

    PubMed Central

    Albers, Christian; Westkott, Maren; Pawelzik, Klaus

    2016-01-01

    Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns. PMID:26900845

  14. The effect of short-term exposure to energy-matched diets enriched in fat or sugar on memory, gut microbiota and markers of brain inflammation and plasticity.

    PubMed

    Beilharz, Jessica E; Kaakoush, Nadeem O; Maniam, Jayanthi; Morris, Margaret J

    2016-10-01

    Short-term exposure to high-energy diets impairs memory but there is little data on the relative contributions of fat and sugar to these deficits or the mechanisms responsible. Here, we investigated how these different macronutrients affect memory, neuroinflammation and neuroplasticity markers and the gut microbiota. Rats were fed matched purified diets for 2weeks; Control, Sugar, Saturated Fatty Acid (SFA) or Polyunsaturated Fatty Acid (PUFA), which varied only in the percentage of energy available from sugar and the amount and type of fat. Rats consuming SFA and Sugar were impaired on hippocampal-dependent place recognition memory compared to Controls and PUFA rats, despite all rats consuming similar amounts of energy. All rats performed comparably on the object recognition task. Hippocampal and hypothalamic inflammatory markers were not substantially affected by the diets and there was no change in the neuroplasticity marker, brain-derived neurotrophic factor. Each of the diets significantly altered the microbial composition in distinct ways. Specifically, the relative abundance of 89 taxa differed significantly between groups with the majority of these changes accounted for by the Clostridiales order and within that, Lachnospiraceae and Ruminococcaceae. These taxa showed a range of macronutrient specific correlations with place memory. In addition, Distance based Linear Models found relationships between memory, inflammation-related hippocampal genes and the gut microbiota. In conclusion, our study shows that the macronutrient profile of the diet is crucial for diet-induced memory deficits and suggests a possible link between diet, the gut microbiota and hippocampal inflammatory genes. PMID:27448745

  15. Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo

    PubMed Central

    2013-01-01

    Background Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored. Results We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis. Conclusions These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity. PMID:24284042

  16. Applicability of the coefficient of variation method for analyzing synaptic plasticity.

    PubMed

    Faber, D S; Korn, H

    1991-11-01

    The classical coefficient of variation method for "quantal" analysis of synaptic responses allows unambiguous identification of pre- and postsynaptic loci underlying synaptic plasticity only when extensive simplifying restrictions are made. They include invariance of quantal parameters and the assumption that a single afferent produces the evoked potentials or currents. More general theoretical formulations and simulations demonstrate that the standard criteria do not always provide useful guidelines because when the other sources of physiological variance are included, putative pre- and postsynaptic domains may overlap. For example, data typically interpreted as indicating modifications at both sites can be due to a mechanism localized to only one of the two, if parameter variances are taken into consideration in the case of a single input cell, or if there are multiple inputs and the stimulus does not activate all of them reliably. With this perspective, other physiologically realistic hypotheses relevant to the expression of synaptic plasticity, such as that during long-term potentiation, can be envisioned.

  17. Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus.

    PubMed

    Bukalo, O; Schachner, M; Dityatev, A

    2001-01-01

    The extracellular matrix is a complex network of macromolecules including glycoproteins, polysaccharides and proteoglycans. Tenascin-R and chondroitin sulfate proteoglycans are essential components of hippocampal extracellular matrix co-localised in perineuronal nets on interneurons. Mutant mice deficient in expression of tenascin-R showed a two-fold reduction of long-term potentiation induced by theta-burst stimulation of Schaffer collaterals in the stratum radiatum of the CA1 region of the hippocampus, as compared to wild-type mice. The same reduction in potentiation was observed in slices from wild-type mice pretreated for 2h with chondroitinase ABC that completely removed chondroitin sulfates from the extracellular matrix. Treatment of slices from tenascin-R deficient animals with the enzyme did not further reduce potentiation in comparison with untreated slices from these mice, showing an occlusion of effects produced by removal of tenascin-R and chondroitin sulfates. However, the level of potentiation recorded immediately after theta-burst stimulation was significantly higher in wild-type than in tenascin-R deficient mice, whereas chondroitinase ABC had no significant effect on this short-term form of plasticity. Enzymatic treatment also did not affect short-term depression evoked by low-frequency stimulation, whereas this form of synaptic plasticity was reduced in tenascin-R deficient mice. In contrast, long-term depression in CA1 was impaired by digestion of chondroitin sulfates but appeared normal in tenascin-R mutants. Our data demonstrate that tenascin-R and chondroitin sulfate proteoglycans differentially modulate several forms of synaptic plasticity, suggesting that different mechanisms are involved.

  18. Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

    PubMed Central

    Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

    2016-01-01

    In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

  19. Enriched environment ameliorates depression-induced cognitive deficits and restores abnormal hippocampal synaptic plasticity.

    PubMed

    Mahati, K; Bhagya, V; Christofer, T; Sneha, A; Shankaranarayana Rao, B S

    2016-10-01

    Severe depression compromises structural and functional integrity of the brain and results in impaired learning and memory, maladaptive synaptic plasticity as well as degenerative changes in the hippocampus and amygdala. The precise mechanisms underlying cognitive dysfunctions in depression remain largely unknown. On the other hand, enriched environment (EE) offers beneficial effects on cognitive functions, synaptic plasticity in the hippocampus. However, the effect of EE on endogenous depression associated cognitive dysfunction has not been explored. Accordingly, we have attempted to address this issue by investigating behavioural, structural and synaptic plasticity mechanisms in an animal model of endogenous depression after exposure to enriched environment. Our results demonstrate that depression is associated with impaired spatial learning and enhanced anxiety-like behaviour which is correlated with hypotrophy of the dentate gyrus and amygdalar hypertrophy. We also observed a gross reduction in the hippocampal long-term potentiation (LTP). We report a complete behavioural recovery with reduced indices of anhedonia and behavioural despair, reduced anxiety-like behaviour and improved spatial learning along with a complete restoration of dentate gyrus and amygdalar volumes in depressive rats subjected to EE. Enrichment also facilitated CA3-Schaffer collateral LTP. Our study convincingly proves that depression-induces learning deficits and impairs hippocampal synaptic plasticity. It also highlights the role of environmental stimuli in restoring depression-induced cognitive deficits which might prove vital in outlining more effective strategies to treat major depressive disorders. PMID:27555234

  20. Environmental Enrichment Ameliorates Neonatal Sevoflurane Exposure-Induced Cognitive and Synaptic Plasticity Impairments.

    PubMed

    Ji, Mu-huo; Wang, Xing-ming; Sun, Xiao-ru; Zhang, Hui; Ju, Ling-sha; Qiu, Li-li; Yang, Jiao-jiao; Jia, Min; Wu, Jing; Yang, Jianjun

    2015-11-01

    Early exposure to sevoflurane, an inhalation anesthetic, induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities. Here, we investigated whether an enriched environment could mitigate neonatal sevoflurane exposure-induced long-term cognitive and synaptic plasticity impairments. Male C57BL/6 mice were exposed to 3 % sevoflurane 2 h daily for 3 days from postnatal day 6 (P6) to P8. The exposed mice were randomly allocated to an enriched environment for 2 h daily between P8 and P42 or to a standard environment. Their behavior and cognition were assessed using open field (P35) and fear conditioning tests (P41-P42). Hematoxylin-eosin staining was used to study morphological changes in pyramidal neurons of hippocampal CA1 and CA3 regions. Synaptic plasticity alternations were assessed using western blotting, Golgi staining, and electrophysiological recording. We found that sevoflurane-exposed mice housed in a standard environment exhibited a reduced freezing response in the contextual test, decreased number of dendritic spines on pyramidal neurons and synaptic plasticity-related proteins in the hippocampus, and impaired long-term potentiation. However, in an enriched environment, some of these abnormities induced by repeated sevoflurane exposure. In conclusion, neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments are ameliorated by an enriched environment.

  1. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I; Tang, Jianrong; Dani, John A

    2015-03-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID:25445492

  2. Long-Term Exercise Is Needed to Enhance Synaptic Plasticity in the Hippocampus

    ERIC Educational Resources Information Center

    Patten, Anna R.; Sickmann, Helle; Hryciw, Brett N.; Kucharsky, Tessa; Parton, Roberta; Kernick, Aimee; Christie, Brian R.

    2013-01-01

    Exercise can have many benefits for the body, but it also benefits the brain by increasing neurogenesis, synaptic plasticity, and performance on learning and memory tasks. The period of exercise needed to realize the structural and functional benefits for the brain have not been well delineated, and previous studies have used periods of exercise…

  3. Environmental Enrichment Ameliorates Neonatal Sevoflurane Exposure-Induced Cognitive and Synaptic Plasticity Impairments.

    PubMed

    Ji, Mu-huo; Wang, Xing-ming; Sun, Xiao-ru; Zhang, Hui; Ju, Ling-sha; Qiu, Li-li; Yang, Jiao-jiao; Jia, Min; Wu, Jing; Yang, Jianjun

    2015-11-01

    Early exposure to sevoflurane, an inhalation anesthetic, induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities. Here, we investigated whether an enriched environment could mitigate neonatal sevoflurane exposure-induced long-term cognitive and synaptic plasticity impairments. Male C57BL/6 mice were exposed to 3 % sevoflurane 2 h daily for 3 days from postnatal day 6 (P6) to P8. The exposed mice were randomly allocated to an enriched environment for 2 h daily between P8 and P42 or to a standard environment. Their behavior and cognition were assessed using open field (P35) and fear conditioning tests (P41-P42). Hematoxylin-eosin staining was used to study morphological changes in pyramidal neurons of hippocampal CA1 and CA3 regions. Synaptic plasticity alternations were assessed using western blotting, Golgi staining, and electrophysiological recording. We found that sevoflurane-exposed mice housed in a standard environment exhibited a reduced freezing response in the contextual test, decreased number of dendritic spines on pyramidal neurons and synaptic plasticity-related proteins in the hippocampus, and impaired long-term potentiation. However, in an enriched environment, some of these abnormities induced by repeated sevoflurane exposure. In conclusion, neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments are ameliorated by an enriched environment. PMID:26227794

  4. Suppression of synaptic plasticity by fullerenol in rat hippocampus in vitro

    PubMed Central

    Wang, Xin-Xing; Zha, Ying-Ying; Yang, Bo; Chen, Lin; Wang, Ming

    2016-01-01

    Fullerenol, a water-soluble fullerene derivative, has attracted much attention due to its bioactive properties, including the antioxidative properties and free radical scavenging ability. Due to its superior nature, fullerenol represents a promising diagnostic, therapeutic, and protective agent. Therefore, elucidation of the possible side effects of fullerenol is important in determining its potential role. In the present study, we investigated the acute effects of 5 μM fullerenol on synaptic plasticity in hippocampal brain slices of rats. Incubation with fullerenol for 20 minutes significantly decreased the peak of paired-pulse facilitation and long-term potentiation, indicating that fullerenol suppresses the short- and long-term synaptic plasticity of region I of hippocampus. We found that fullerenol depressed the activity and the expression of nitric oxide (NO) synthase in hippocampus. In view of the important role of NO in synaptic plasticity, the inhibition of fullerenol on NO synthase may contribute to the suppression of synaptic plasticity. These findings may facilitate the evaluation of the side effects of fullerenol. PMID:27729790

  5. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I; Tang, Jianrong; Dani, John A

    2015-03-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.

  6. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    ERIC Educational Resources Information Center

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  7. A role for reactive oxygen/nitrogen species and iron on neuronal synaptic plasticity.

    PubMed

    Hidalgo, Cecilia; Carrasco, M Angélica; Muñoz, Pablo; Núñez, Marco T

    2007-02-01

    A great body of experimental evidence collected over many years indicates that calcium has a central role in a variety of neuronal functions. In particular, calcium participates in synaptic plasticity, a neuronal process presumably correlated with cognitive brain functions such as learning and memory. In contrast, only recently, evidence has begun to emerge supporting a physiological role of reactive oxygen (ROS) and nitrogen (RNS) species in synaptic plasticity. This subject will be the central topic of this review. The authors also present recent results showing that, in hippocampal neurons, ROS/RNS, including ROS generated by iron through the Fenton reaction, stimulate ryanodine receptor-mediated calcium release, and how the resulting calcium signals activate the signaling cascades that lead to the transcription of genes known to participate in synaptic plasticity. They discuss the possible participation of ryanodine receptors jointly stimulated by calcium and ROS/RNS in the normal signaling cascades needed for synaptic plasticity, and how too much ROS production may contribute to neurodegeneration via excessive calcium release. In addition, the dual role of iron as a necessary, but potentially toxic, element for normal neuronal function is discussed. PMID:17115937

  8. Impairment of Select Forms of Spatial Memory and Neurotrophin-Dependent Synaptic Plasticity by Deletion of Glial Aquaporin-4

    PubMed Central

    Skucas, Vanessa A.; Mathews, Ian B.; Yang, Jianmin; Cheng, Qi; Treister, Andrew; Verkman, Alan S.; Hempstead, Barbara L.; Wood, Marcelo A.; Binder, Devin K.; Scharfman, Helen E.

    2011-01-01

    Aquaporin-4 (AQP4) is the major water channel in the central nervous system (CNS) and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP), and long-term depression (LTD) in AQP4 knockout (KO) and wild type (WT) mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm (TBS-LTP), but there was no impairment in a form of LTP that is BDNF-independent, induced by high frequency stimulation (HFS-LTP). LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior. PMID:21525279

  9. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex

    PubMed Central

    Lalo, U.; Palygin, O.; Verkhratsky, A.; Grant, S. G. N.; Pankratov, Y.

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca2+-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca2+-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  10. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex.

    PubMed

    Lalo, U; Palygin, O; Verkhratsky, A; Grant, S G N; Pankratov, Y

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca(2+)-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca(2+)-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  11. Restless AMPA receptors: implications for synaptic transmission and plasticity

    PubMed Central

    Lüscher, Christian; Frerking, Matthew

    2010-01-01

    A central assumption in neurobiology holds that changes in the strength of individual synapses underlie changes in behavior. This concept is widely accepted in the case of learning and memory where LTP and LTD are the most compelling cellular models. It is therefore of great interest to understand, on a molecular level, how the brain regulates the strength of neuronal connections. We review a large body of evidence in support of the very straightforward regulation of synaptic strength by changing the number of postsynaptic receptors, and discuss the molecular machinery required for insertion and removal of AMPA receptors. PMID:11672812

  12. Enriched environment improves synaptic plasticity and cognitive deficiency in chronic cerebral hypoperfused rats.

    PubMed

    Bayat, Mahnaz; Sharifi, Mohammad Davood; Haghani, Masoud; Shabani, Mohammad

    2015-10-01

    Recent studies have indicated that environmental enrichment (EE) increases the sensorial and social stimulations and leads to strengthened plastic changes in the brain. In models of chronic cerebral hypoperfusion, the ability of an EE to restore the cognition depends on hippocampal synaptic plasticity. The mechanisms for this effect have not, however, been adequately studied. Thus, the aim of the present study was to evaluate the neuroprotective effects and underlying mechanism of environmental enrichment by assessment of spatial memory tasks as well as parameters of synaptic plasticity in rats subjected to occlusion of the bilateral common carotid arteries (2-VO) model. Male Sprague-Dawley rats were used in this study. The model group was established by occlusion of the bilateral common carotid arteries. The animals were tested for learning, memory performance and synaptic plasticity using Morris water maze (MWM), 8-arm Radial Maze (RM), and field potential recording, respectively. The rats subjected to 2-VO in EE exhibited a significantly lower number of working errors and reference errors in RM. Moreover, the enriched environment recovered the memory performance of hypoperfused rats and decreased the swimming time to reach the platform in MWM. In addition, conditions of the environment did not have any effect on baseline synaptic transmission and presynaptic plasticity, but housing the animals in EE rescued the impairment of LTP induction induced by 2-VO. These results suggest that EE ameliorates the LTP and spatial memory impairment induced by 2-VO. Our data indicated that the LTP recovery by EE in the rat models of 2-VO is probably mediated by post-synaptic mechanisms.

  13. Associative Hebbian Synaptic Plasticity in Primate Visual Cortex

    PubMed Central

    Huang, Shiyong; Rozas, Carlos; Treviño, Mario; Contreras, Jessica; Yang, Sunggu; Song, Lihua; Yoshioka, Takashi; Lee, Hey-Kyoung

    2014-01-01

    In primates, the functional connectivity of adult primary visual cortex is susceptible to be modified by sensory training during perceptual learning. It is widely held that this type of neural plasticity might involve mechanisms like long-term potentiation (LTP) and long-term depression (LTD). NMDAR-dependent forms of LTP and LTD are particularly attractive because in rodents they can be induced in a Hebbian manner by near coincidental presynaptic and postsynaptic firing, in a paradigm termed spike timing-dependent plasticity (STDP). These fundamental properties of LTP and LTD, Hebbian induction and NMDAR dependence, have not been examined in primate cortex. Here we demonstrate these properties in the primary visual cortex of the rhesus macaque (Macaca mulatta), and also show that, like in rodents, STDP is gated by neuromodulators. These findings indicate that the cellular principles governing cortical plasticity are conserved across mammalian species, further validating the use of rodents as a model system. PMID:24872561

  14. Stable learning of functional maps in self-organizing spiking neural networks with continuous synaptic plasticity

    PubMed Central

    Srinivasa, Narayan; Jiang, Qin

    2013-01-01

    This study describes a spiking model that self-organizes for stable formation and maintenance of orientation and ocular dominance maps in the visual cortex (V1). This self-organization process simulates three development phases: an early experience-independent phase, a late experience-independent phase and a subsequent refinement phase during which experience acts to shape the map properties. The ocular dominance maps that emerge accommodate the two sets of monocular inputs that arise from the lateral geniculate nucleus (LGN) to layer 4 of V1. The orientation selectivity maps that emerge feature well-developed iso-orientation domains and fractures. During the last two phases of development the orientation preferences at some locations appear to rotate continuously through ±180° along circular paths and referred to as pinwheel-like patterns but without any corresponding point discontinuities in the orientation gradient maps. The formation of these functional maps is driven by balanced excitatory and inhibitory currents that are established via synaptic plasticity based on spike timing for both excitatory and inhibitory synapses. The stability and maintenance of the formed maps with continuous synaptic plasticity is enabled by homeostasis caused by inhibitory plasticity. However, a prolonged exposure to repeated stimuli does alter the formed maps over time due to plasticity. The results from this study suggest that continuous synaptic plasticity in both excitatory neurons and interneurons could play a critical role in the formation, stability, and maintenance of functional maps in the cortex. PMID:23450808

  15. Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association.

    PubMed

    Lee, Junuk; Finkelstein, Joel; Choi, Jung Yoon; Witten, Ilana B

    2016-06-01

    Despite the fact that cholinergic interneurons are a key cell type within the nucleus accumbens, a relationship between synaptic plasticity and the in vivo activity of cholinergic interneurons remains to be established. Here, we identify a three-way link between the activity of cholinergic interneurons, synaptic plasticity, and learning in mice undergoing the extinction of a cocaine-context association. We found that activity of cholinergic interneurons regulates extinction learning for a cocaine-context association and generates a sustained reduction in glutamatergic presynaptic strength onto medium spiny neurons. Interestingly, activation of cholinergic interneurons does not support reinforcement learning or plasticity by itself, suggesting that these neurons have a modulatory rather than a reinforcing function. PMID:27210555

  16. Self-organization of a recurrent network under ongoing synaptic plasticity.

    PubMed

    Aoki, Takaaki

    2015-02-01

    We investigated the organization of a recurrent network under ongoing synaptic plasticity using a model of neural oscillators coupled by dynamic synapses. In this model, the coupling weights changed dynamically, depending on the timing between the oscillators. We determined the phase coupling function of the oscillator model, Γ(ϕ), using conductance-based neuron models. Furthermore, we examined the effects of the Fourier zero mode of Γ(ϕ), which has a critical role in the case of spike-time-dependent plasticity-organized recurrent networks. Heterogeneous layered clusters with different frequencies emerged from homogeneous populations as the Fourier zero mode increased. Our findings may provide new insights into the self-assembly mechanisms of neural networks related to synaptic plasticity.

  17. Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling.

    PubMed

    Cahill, Michael E; Bagot, Rosemary C; Gancarz, Amy M; Walker, Deena M; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A; Feng, Jian; Kennedy, Pamela J; Koo, Ja Wook; Cates, Hannah M; Neve, Rachael L; Shen, Li; Dietz, David M; Nestler, Eric J

    2016-02-01

    Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

  18. Activity-Dependent Synaptic Plasticity of a Chalcogenide Electronic Synapse for Neuromorphic Systems

    NASA Astrophysics Data System (ADS)

    Li, Yi; Zhong, Yingpeng; Zhang, Jinjian; Xu, Lei; Wang, Qing; Sun, Huajun; Tong, Hao; Cheng, Xiaoming; Miao, Xiangshui

    2014-05-01

    Nanoscale inorganic electronic synapses or synaptic devices, which are capable of emulating the functions of biological synapses of brain neuronal systems, are regarded as the basic building blocks for beyond-Von Neumann computing architecture, combining information storage and processing. Here, we demonstrate a Ag/AgInSbTe/Ag structure for chalcogenide memristor-based electronic synapses. The memristive characteristics with reproducible gradual resistance tuning are utilised to mimic the activity-dependent synaptic plasticity that serves as the basis of memory and learning. Bidirectional long-term Hebbian plasticity modulation is implemented by the coactivity of pre- and postsynaptic spikes, and the sign and degree are affected by assorted factors including the temporal difference, spike rate and voltage. Moreover, synaptic saturation is observed to be an adjustment of Hebbian rules to stabilise the growth of synaptic weights. Our results may contribute to the development of highly functional plastic electronic synapses and the further construction of next-generation parallel neuromorphic computing architecture.

  19. Neurexin-1 regulates sleep and synaptic plasticity in Drosophila melanogaster.

    PubMed

    Larkin, Aoife; Chen, Ming-Yu; Kirszenblat, Leonie; Reinhard, Judith; van Swinderen, Bruno; Claudianos, Charles

    2015-10-01

    Neurexins are cell adhesion molecules that are important for synaptic plasticity and homeostasis, although links to sleep have not yet been investigated. We examined the effects of neurexin-1 perturbation on sleep in Drosophila, showing that neurexin-1 nulls displayed fragmented sleep and altered circadian rhythm. Conversely, the over-expression of neurexin-1 could increase and consolidate night-time sleep. This was not solely due to developmental effects as it could be induced acutely in adulthood, and was coupled with evidence of synaptic growth. The timing of over-expression could differentially impact sleep patterns, with specific night-time effects. These results show that neurexin-1 was dynamically involved in synaptic plasticity and sleep in Drosophila. Neurexin-1 and a number of its binding partners have been repeatedly associated with mental health disorders, including autism spectrum disorders, schizophrenia and Tourette syndrome, all of which are also linked to altered sleep patterns. How and when plasticity-related proteins such as neurexin-1 function during sleep can provide vital information on the interaction between synaptic homeostasis and sleep, paving the way for more informed treatments of human disorders.

  20. Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity.

    PubMed

    Gerber, Kyle J; Squires, Katherine E; Hepler, John R

    2016-02-01

    The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Gα subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre- and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

  1. Activity-Dependent Synaptic Plasticity of a Chalcogenide Electronic Synapse for Neuromorphic Systems

    PubMed Central

    Li, Yi; Zhong, Yingpeng; Zhang, Jinjian; Xu, Lei; Wang, Qing; Sun, Huajun; Tong, Hao; Cheng, Xiaoming; Miao, Xiangshui

    2014-01-01

    Nanoscale inorganic electronic synapses or synaptic devices, which are capable of emulating the functions of biological synapses of brain neuronal systems, are regarded as the basic building blocks for beyond-Von Neumann computing architecture, combining information storage and processing. Here, we demonstrate a Ag/AgInSbTe/Ag structure for chalcogenide memristor-based electronic synapses. The memristive characteristics with reproducible gradual resistance tuning are utilised to mimic the activity-dependent synaptic plasticity that serves as the basis of memory and learning. Bidirectional long-term Hebbian plasticity modulation is implemented by the coactivity of pre- and postsynaptic spikes, and the sign and degree are affected by assorted factors including the temporal difference, spike rate and voltage. Moreover, synaptic saturation is observed to be an adjustment of Hebbian rules to stabilise the growth of synaptic weights. Our results may contribute to the development of highly functional plastic electronic synapses and the further construction of next-generation parallel neuromorphic computing architecture. PMID:24809396

  2. Orexin Signaling in the VTA Gates Morphine-Induced Synaptic Plasticity.

    PubMed

    Baimel, Corey; Borgland, Stephanie L

    2015-05-01

    Dopamine neurons in the ventral tegmental area (VTA) are a key target of addictive drugs, and neuroplasticity in this region may underlie some of the core features of addiction. From the very first exposure, all drugs of abuse induce synaptic plasticity in the VTA. However, it is not well understood how this diverse group of drugs brings about common synaptic change. Orexin (also known as hypocretin) is a lateral hypothalamic neuropeptide released into the VTA that promotes drug-seeking behaviors and potentiates excitatory synaptic transmission onto VTA dopamine neurons. Here we show that signaling at orexin receptor type 1 (OxR1) in the VTA is required for morphine-induced plasticity of dopamine neurons. Systemic or intra-VTA administration of the OxR1 antagonist SB 334867 in rats blocked a morphine-induced increase in the AMPAR/NMDAR ratio, an increase in presynaptic glutamate release, and a postsynaptic change in AMPAR number or function, including a switch in subunit composition. Furthermore, SB 334867 blocked a morphine-induced decrease in presynaptic GABA release, and a morphine-induced shift in the balance of excitatory and inhibitory synaptic inputs to dopamine neurons. These findings identify a novel role for orexin in morphine-induced plasticity in the VTA and provide a mechanism by which orexin can gate the output of dopamine neurons.

  3. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging.

    PubMed

    Henley, Jeremy M; Wilkinson, Kevin A

    2013-03-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease.

  4. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

    PubMed Central

    Henley, Jeremy M.; Wilkinson, Kevin A.

    2013-01-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease. PMID:23576886

  5. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    PubMed Central

    Soheili, Masoud; Tavirani, Mostafa Rezaei; Salami, Mahmoud

    2015-01-01

    Objective(s): Neurodegenerative Alzheimer’s disease (AD) is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP), an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia) on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extracellular postsynaptic potentials (fEPSPs) were recorded in the CA1 area. Materials and Methods: The electrophysiological recordings were carried out in four groups of rats; two control groups including the vehicle (CON) and lavender (CE) treated rats and two Alzheimeric groups including the vehicle (ALZ) and lavender (AE) treated animals. Results: The extract inefficiently affected the baseline responses in the four testing groups. While the fEPSPs displayed a considerable LTP in the CON animals, no potentiation was evident in the tetanized responses in the ALZ rats. The herbal medicine effectively restored LTP in the AE group and further potentiated fEPSPs in the CE group. Conclusion: The positive effect of the lavender extract on the plasticity of synaptic transmission supports its previously reported behavioral effects on improvement of impaired spatial memory in the Alzheimeric animals. PMID:26949505

  6. Prior regular exercise prevents synaptic plasticity impairment in sleep deprived female rats.

    PubMed

    Saadati, Hakimeh; Sheibani, Vahid; Esmaeili-Mahani, Saeed; Hajali, Vahid; Mazhari, Shahrzad

    2014-09-01

    Previous studies have indicated that physical exercise plays a preventive role in synaptic plasticity deficits in the hippocampus of sleep-deprived male rats. The objective of the present study was to evaluate the effects of treadmill running on early long term potentiation (E-LTP) at the Cornu Ammonis (CA1) area of the hippocampus in sleep-deprived female rats. Intact and ovariectomiezed (OVX) female Wistar rats were used in the present study. The exercise protocol was four weeks treadmill running and the multiple platform method was applied to induce 72 h sleep deprivation (SD). We examine the effect of exercise and/or SD on synaptic plasticity using in vivo extracellular recording in the CA1 area of the hippocampus. The field excitatory post-synaptic potential (fEPSP) slope was measured before and 2h after high frequency stimulation (HFS) in the experimental groups. Field potential recording indicated that the induction and maintenance phase of E-LTP impaired in the sleep deprived animals compared to the other groups. After 72 h SD, E-LTP impairments were prevented by 4 weeks of regular treadmill exercise. In conclusion, the synaptic plasticity deficit in sleep-deprived female rats was improved by regular physical exercise. Further studies are suggested to evaluate the possible underlying mechanisms.

  7. Effects of pre-natal alcohol exposure on hippocampal synaptic plasticity: Sex, age and methodological considerations.

    PubMed

    Fontaine, Christine J; Patten, Anna R; Sickmann, Helle M; Helfer, Jennifer L; Christie, Brian R

    2016-05-01

    The consumption of alcohol during gestation is detrimental to the developing central nervous system (CNS). The severity of structural and functional brain alterations associated with alcohol intake depends on many factors including the timing and duration of alcohol consumption. The hippocampal formation, a brain region implicated in learning and memory, is highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on learning and memory may be due to changes at the synaptic level, as this teratogen has been repeatedly shown to interfere with hippocampal synaptic plasticity. At the molecular level alcohol interferes with receptor proteins and can disrupt hormones that are important for neuronal signaling and synaptic plasticity. In this review we examine the consequences of prenatal and early postnatal alcohol exposure on hippocampal synaptic plasticity and highlight the numerous factors that can modulate the effects of alcohol. We also discuss some potential mechanisms responsible for these changes as well as emerging therapeutic avenues that are beginning to be explored. PMID:26906760

  8. Pregnenolone sulfate as a modulator of synaptic plasticity

    PubMed Central

    Smith, Conor C.; Gibbs, Terrell T.

    2015-01-01

    Rationale The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update. Results Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca2+- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~2 pM) direct enhancement of intracellular Ca2+ levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed. Conclusions PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification. PMID:24997854

  9. Rapid neural circuit switching mediated by synaptic plasticity during neural morphallactic regeneration.

    PubMed

    Lybrand, Zane R; Zoran, Mark J

    2012-09-01

    The aquatic oligochaete, Lumbriculus variegatus (Lumbriculidae), undergoes a rapid regenerative transformation of its neural circuits following body fragmentation. This type of nervous system plasticity, called neural morphallaxis, involves the remodeling of the giant fiber pathways that mediate rapid head and tail withdrawal behaviors. Extra- and intracellular electrophysiological recordings demonstrated that changes in cellular properties and synaptic connections underlie neurobehavioral plasticity during morphallaxis. Sensory-to-giant interneuron connections, undetectable prior to body injury, emerged within hours of segment amputation. The appearance of functional synaptic transmission was followed by interneuron activation, coupling of giant fiber spiking to motor outputs and overt segmental shortening. The onset of morphallactic plasticity varied along the body axis and emerged more rapidly in segments closer to regions of sensory field overlap between the two giant fiber pathways. The medial and lateral giant fibers were simultaneously activated during a transient phase of network remodeling. Thus, synaptic plasticity at sensory-to-giant interneuron connections mediates escape circuit morphallaxis in this regenerating annelid worm. PMID:22021133

  10. MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity

    PubMed Central

    Hou, Qingming; Ruan, Hongyu; Gilbert, James; Wang, Guan; Ma, Qi; Yao, Wei-Dong; Man, Heng-Ye

    2015-01-01

    Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3′-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity. PMID:26620774

  11. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats

    PubMed Central

    Díaz, Paula; Ardiles, Álvaro O.

    2016-01-01

    Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP. PMID:27493805

  12. The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

    PubMed Central

    Aarse, Janna; Herlitze, Stefan

    2016-01-01

    ABSTRACT Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF+/−). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF+/− mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF+/− mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus

  13. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment.

    PubMed

    Yang, Miyoung; Kim, Juhwan; Kim, Sung-Ho; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

    2012-07-25

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  14. Possible Contributions of a Novel Form of Synaptic Plasticity in "Aplysia" to Reward, Memory, and Their Dysfunctions in Mammalian Brain

    ERIC Educational Resources Information Center

    Hawkins, Robert D.

    2013-01-01

    Recent studies in "Aplysia" have identified a new variation of synaptic plasticity in which modulatory transmitters enhance spontaneous release of glutamate, which then acts on postsynaptic receptors to recruit mechanisms of intermediate- and long-term plasticity. In this review I suggest the hypothesis that similar plasticity occurs in…

  15. The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease.

    PubMed

    Gu, Xun-Hu; Xu, Li-Jun; Liu, Zhi-Qiang; Wei, Bo; Yang, Yuan-Jian; Xu, Guo-Gang; Yin, Xiao-Ping; Wang, Wei

    2016-09-15

    Increasing evidence suggests that disruptions of synaptic functions correlate with the severity of cognitive deficit in Alzheimer's disease (AD). Our previous study demonstrated that baicalein enhances long-term potentiation (LTP) in acute rat hippocampal slices and improves hippocampus-dependent contextual fear conditioning in rats. Given that baicalein possess various biological activities, especially its effects on synaptic plasticity and cognitive function, we examined the effect of baicalein on synaptic function both in vitro and in vivo in AD model. The effect of baicalein on Aβ42 oligomer impaired LTP was investigated by electrophysiological methods. Baicalein was administered orally via drinking water to the APP/PS1 mice and sex- and age-matched wild-type mice. Treatment started at 5 months of age and mice were assessed for cognition and AD-like pathology at 7-month-old. Cognition was analyzed by Morris water maze test, fear conditioning test, and novel object recognition test. Changes in hippocampal 12/15 Lipoxygenase (12/15LO) and glycogen synthase kinase 3β (GSK3β) activity, Aβ production, tau phosphorylation, synaptic plasticity, and dendritic spine density were evaluated. Baicalein prevented Aβ-induced impairments in hippocampal LTP through activation of serine threonine Kinase (Akt) phosphorylation. Long-term oral administration of baicalein inhibited 12/15LO and GSK3β activity, reduced β-secretase enzyme (BACE1), decreased the concentration of total Aβ, and prevented phosphorylation of tau in APP/PS1 mice. Meanwhile, baicalein restored spine number, synaptic plasticity, and memory deficits. Our results strengthen the potential of the flavonoid baicalein as a novel and promising oral bioactive therapeutic agent that prevents memory deficits in AD.

  16. Telencephalic neurocircuitry and synaptic plasticity in rodent spatial learning and memory.

    PubMed

    Pooters, Tine; Van der Jeugd, Ann; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi

    2015-09-24

    Spatial learning and memory in rodents represent close equivalents of human episodic declarative memory, which is especially sensitive to cerebral aging, neurodegeneration, and various neuropsychiatric disorders. Many tests and protocols are available for use in laboratory rodents, but Morris water maze and radial-arm maze remain the most widely used as well as the most valid and reliable spatial tests. Telencephalic neurocircuitry that plays functional roles in spatial learning and memory includes hippocampus, dorsal striatum and medial prefrontal cortex. Prefrontal-hippocampal circuitry comprises the major associative system in the rodent brain, and is critical for navigation in physical space, whereas interconnections between prefrontal cortex and dorsal striatum are probably more important for motivational or goal-directed aspects of spatial learning. Two major forms of synaptic plasticity, namely long-term potentiation, a lasting increase in synaptic strength between simultaneously activated neurons, and long-term depression, a decrease in synaptic strength, have been found to occur in hippocampus, dorsal striatum and medial prefrontal cortex. These and other phenomena of synaptic plasticity are probably crucial for the involvement of telencephalic neurocircuitry in spatial learning and memory. They also seem to play a role in the pathophysiology of two brain pathologies with episodic declarative memory impairments as core symptoms, namely Alzheimer's disease and schizophrenia. Further research emphasis on rodent telencephalic neurocircuitry could be relevant to more valid and reliable preclinical research on these most devastating brain disorders. This article is part of a Special Issue entitled SI: Brain and Memory.

  17. Gene expression parallels synaptic excitability and plasticity changes in Alzheimer’s disease

    PubMed Central

    Saura, Carlos A.; Parra-Damas, Arnaldo; Enriquez-Barreto, Lilian

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders. PMID:26379494

  18. Regulation of cpg15 by signaling pathways that mediate synaptic plasticity.

    PubMed

    Fujino, Tadahiro; Lee, Wei-Chung Allen; Nedivi, Elly

    2003-11-01

    Transcriptional activation is a key link between neuronal activity and long-term synaptic plasticity. Little is known about genes responding to this activation whose products directly effect functional and structural changes at the synapse. cpg15 is an activity-regulated gene encoding a membrane-bound ligand that regulates dendritic and axonal arbor growth and synaptic maturation. We report that cpg15 is an immediate-early gene induced by Ca(2+) influx through NMDA receptors and L-type voltage-sensitive calcium channels. Activity-dependent cpg15 expression requires convergent activation of the CaM kinase and MAP kinase pathways. Although activation of PKA is not required for activity-dependent expression, cpg15 is induced by cAMP in active neurons. CREB binds the cpg15 promoter in vivo and partially regulates its activity-dependent expression. cpg15 is an effector gene that is a target for signal transduction pathways that mediate synaptic plasticity and thus may take part in an activity-regulated transcriptional program that directs long-term changes in synaptic connections. PMID:14664806

  19. Acute and chronic effects of ethanol on learning-related synaptic plasticity.

    PubMed

    Zorumski, Charles F; Mennerick, Steven; Izumi, Yukitoshi

    2014-02-01

    Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol's acute and long-term pharmacological consequences.

  20. Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice.

    PubMed

    Jia, Jian-Xin; Cui, Cheng-Li; Yan, Xu-Sheng; Zhang, Bai-Feng; Song, Wei; Huo, Dong-Sheng; Wang, He; Yang, Zhan-Jun

    2016-01-01

    Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot. T significantly increased the dendritic spine density in hippocampal CA1 region, while flutamide (F) inhibited these T-mediated effects. Immunohistochemistry and western blot analysis showed that the expression levels of brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD-95), and p-cyclic-AMP response element binding protein (CREB)/CREB levels were significantly elevated in the T group, but F reduced the T-induced effects in these biomarkers to control levels. There were no significant differences in the expression levels of PSD-95, BDNF, and p-CREB/CREB between C and F. These findings indicate that the effects of T on improvement in synaptic plasticity were mediated via androgen receptor (AR). It is conceivable that new treatments targeted toward preventing synaptic pathology in AD may involve the use of androgen-acting drugs. PMID:27599230

  1. Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity

    PubMed Central

    Tigaret, Cezar M.; Olivo, Valeria; Sadowski, Josef H.L.P.; Ashby, Michael C.; Mellor, Jack R.

    2016-01-01

    At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function. PMID:26758963

  2. Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

    PubMed

    Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-11-05

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact.

  3. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    PubMed Central

    Shen, Ling-ling; Jiang, Ming-liang; Liu, Si-si; Cai, Min-chun; Hong, Zhong-qiu; Lin, Li-qing; Xing, Yan-yan; Chen, Gui-lin; Pan, Rui; Yang, Li-juan; Xu, Ying; Dong, Jun

    2015-01-01

    Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug. PMID:26199609

  4. Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

    PubMed

    Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-01-01

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact. PMID:25377939

  5. Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration

    PubMed Central

    Tononi, Giulio; Cirelli, Chiara

    2014-01-01

    Summary Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain. This increases cellular needs for energy and supplies, decreases signal-to-noise ratios, and saturates learning. During sleep, spontaneous activity renormalizes net synaptic strength and restores cellular homeostasis. Activity-dependent down-selection of synapses can also explain the benefits of sleep on memory acquisition, consolidation, and integration. This happens through the off-line, comprehensive sampling of statistical regularities incorporated in neuronal circuits over a lifetime. This review considers the rationale and evidence for SHY and points to open issues related to sleep and plasticity. PMID:24411729

  6. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    PubMed Central

    Guzman, Segundo J.; Gerevich, Zoltan

    2016-01-01

    ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states. PMID:27069691

  7. Low-frequency transcranial magnetic stimulation is beneficial for enhancing synaptic plasticity in the aging brain

    PubMed Central

    Zhang, Zhan-chi; Luan, Feng; Xie, Chun-yan; Geng, Dan-dan; Wang, Yan-yong; Ma, Jun

    2015-01-01

    In the aging brain, cognitive function gradually declines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation (≤1 Hz) ameliorates synaptic plasticity and spatial cognitive deficits in learning-impaired mice. However, the mechanisms by which this treatment improves these deficits during normal aging are still unknown. Therefore, the current study investigated the effects of transcranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, synaptophysin and growth-associated protein 43 (both synaptic markers), to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcranial magnetic stimulation with low intensity (110% average resting motor threshold intensity, 1 Hz) increased mRNA and protein levels of brain-derived neurotrophic factor, tropomyosin receptor kinase B, and Fyn in the hippocampus of aged mice. The treatment also upregulated the mRNA and protein expression of synaptophysin and growth-associated protein 43 in the hippocampus of these mice. In conclusion, brain-derived neurotrophic factor signaling may play an important role in sustaining and regulating structural synaptic plasticity induced by transcranial magnetic stimulation in the hippocampus of aging mice, and Fyn may be critical during this regulation. These responses may change the structural plasticity of the aging hippocampus, thereby improving cognitive function. PMID:26199608

  8. Does Spike-Timing-Dependent Synaptic Plasticity Couple or Decouple Neurons Firing in Synchrony?

    PubMed Central

    Knoblauch, Andreas; Hauser, Florian; Gewaltig, Marc-Oliver; Körner, Edgar; Palm, Günther

    2012-01-01

    Spike synchronization is thought to have a constructive role for feature integration, attention, associative learning, and the formation of bidirectionally connected Hebbian cell assemblies. By contrast, theoretical studies on spike-timing-dependent plasticity (STDP) report an inherently decoupling influence of spike synchronization on synaptic connections of coactivated neurons. For example, bidirectional synaptic connections as found in cortical areas could be reproduced only by assuming realistic models of STDP and rate coding. We resolve this conflict by theoretical analysis and simulation of various simple and realistic STDP models that provide a more complete characterization of conditions when STDP leads to either coupling or decoupling of neurons firing in synchrony. In particular, we show that STDP consistently couples synchronized neurons if key model parameters are matched to physiological data: First, synaptic potentiation must be significantly stronger than synaptic depression for small (positive or negative) time lags between presynaptic and postsynaptic spikes. Second, spike synchronization must be sufficiently imprecise, for example, within a time window of 5–10 ms instead of 1 ms. Third, axonal propagation delays should not be much larger than dendritic delays. Under these assumptions synchronized neurons will be strongly coupled leading to a dominance of bidirectional synaptic connections even for simple STDP models and low mean firing rates at the level of spontaneous activity. PMID:22936909

  9. Preservation of Long-Term Memory and Synaptic Plasticity Despite Short-Term Impairments in the Tc1 Mouse Model of Down Syndrome

    ERIC Educational Resources Information Center

    Morice, Elise; Andreae, Laura C.; Cooke, Sam F.; Vanes, Lesley; Fisher, Elizabeth M. C.; Tybulewicz, Victor L. J.; Bliss, Timothy V. P.

    2008-01-01

    Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a…

  10. PERSISTENT IMPAIRMENTS IN SHORT-TERM BUT ENHANCED LONG-TERM SYNAPTIC PLASTICITY IN HIPPOCAMPAL AREA CA1 FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM.

    EPA Science Inventory

    Thyroid hormones (TH) are critical for nervous system development. Deficiency of TH during development impair performance on tasks of learning and memory that rely upon the hippocampus, but the mechanism underlying this impairment is not well understood. The present study was ...

  11. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum.

    PubMed

    Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel; Pozo, Karine; Plattner, Florian; Bibb, James A

    2016-01-01

    The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum. PMID:27443506

  12. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum.

    PubMed

    Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel; Pozo, Karine; Plattner, Florian; Bibb, James A

    2016-07-22

    The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum.

  13. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum

    PubMed Central

    Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel; Pozo, Karine; Plattner, Florian; Bibb, James A.

    2016-01-01

    The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum. PMID:27443506

  14. Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

    PubMed Central

    Klann, Eric

    2011-01-01

    Abstract The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age- or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function. Antioxid. Redox Signal. 14, 2013–2054. PMID:20649473

  15. Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.

    PubMed

    Glen, W Bailey; Horowitz, Bryant; Carlson, Gregory C; Cannon, Tyrone D; Talbot, Konrad; Jentsch, J David; Lavin, Antonieta

    2014-02-01

    Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia. PMID:24446171

  16. Ovariectomy does not exacerbate the negative effects of sleep deprivation on synaptic plasticity in rats.

    PubMed

    Hajali, Vahid; Sheibani, Vahid; Mahani, Saeed E; Hajializadeh, Zahra; Shabani, Mohammad; Aliabadi, Hamzeh P; Saadati, Hakimeh; Esmaeilpour, Khadijeh

    2015-05-15

    In our previous work, we found that female rats showed more cognitive impairment than male rats following 72h sleep deprivation (SD). Here, we compared the intact female with ovariectomized (OVX) rats to assess the potential modulatory effects of endogenous female sex hormones against the 48h SD-induced cognitive and synaptic modulations. The multiple platform method was applied for SD induction and spatial performances were determined using Morris water maze (MWM) task. Early longterm potentiation (E-LTP) was evaluated in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess hippocampal BDNF gene and protein expression. To reveal any influence of sleep loss on stress level, we also measured the plasma corticosterone levels of animals. Regardless of reproductive status, SD significantly impaired short-term memory and LTP, but did not significantly change the BDNF expression in the hippocampus. The corticosterone levels were decreased in both intact and OVX female rats following SD. These findings suggest that depletion of female sex steroid hormones does not lead to any heightened responsivity of female animals to the negative effects of SD on cognitive and synaptic functions. PMID:25748255

  17. Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression.

    PubMed

    Mancini, Maria; Ghiglieri, Veronica; Bagetta, Vincenza; Pendolino, Valentina; Vannelli, Anna; Cacace, Fabrizio; Mineo, Desireé; Calabresi, Paolo; Picconi, Barbara

    2016-02-01

    Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.

  18. Signaling Pathways Involved in Striatal Synaptic Plasticity are Sensitive to Temporal Pattern and Exhibit Spatial Specificity

    PubMed Central

    Kim, BoHung; Hawes, Sarah L.; Gillani, Fawad; Wallace, Lane J.; Blackwell, Kim T.

    2013-01-01

    The basal ganglia is a brain region critically involved in reinforcement learning and motor control. Synaptic plasticity in the striatum of the basal ganglia is a cellular mechanism implicated in learning and neuronal information processing. Therefore, understanding how different spatio-temporal patterns of synaptic input select for different types of plasticity is key to understanding learning mechanisms. In striatal medium spiny projection neurons (MSPN), both long term potentiation (LTP) and long term depression (LTD) require an elevation in intracellular calcium concentration; however, it is unknown how the post-synaptic neuron discriminates between different patterns of calcium influx. Using computer modeling, we investigate the hypothesis that temporal pattern of stimulation can select for either endocannabinoid production (for LTD) or protein kinase C (PKC) activation (for LTP) in striatal MSPNs. We implement a stochastic model of the post-synaptic signaling pathways in a dendrite with one or more diffusionally coupled spines. The model is validated by comparison to experiments measuring endocannabinoid-dependent depolarization induced suppression of inhibition. Using the validated model, simulations demonstrate that theta burst stimulation, which produces LTP, increases the activation of PKC as compared to 20 Hz stimulation, which produces LTD. The model prediction that PKC activation is required for theta burst LTP is confirmed experimentally. Using the ratio of PKC to endocannabinoid production as an index of plasticity direction, model simulations demonstrate that LTP exhibits spine level spatial specificity, whereas LTD is more diffuse. These results suggest that spatio-temporal control of striatal information processing employs these Gq coupled pathways. PMID:23516346

  19. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    PubMed Central

    Janc, Oliwia A.; Müller, Michael

    2014-01-01

    Rett syndrome (RS) causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2 (methyl-CpG-binding protein 2)-deficient mouse (Mecp2-/y) hippocampus confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3–5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved synaptic short-term plasticity, and fully restored synaptic long-term potentiation (LTP). Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves the hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation. PMID:24605086

  20. Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses onto interneurons

    PubMed Central

    Galván, Emilio J.; Cosgrove, Kathleen E.; Barrionuevo, Germán

    2010-01-01

    The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells with inhibitory interneurons has emerged. These data have revealed an immense heterogeneity of long-term plasticity at MF synapses on various interneuron targets. Interestingly, these studies also indicate that the mechanisms of MF long-term plasticity in some interneuron subtypes may be more similar to pyramidal cells than previously appreciated. In this review, we first define the synapse types at each of the interneuron targets based on the receptors present. We then describe the different forms of long-term plasticity observed, and the mechanisms underlying each form as they are currently understood. Finally we highlight various open questions surrounding MF long-term plasticity in interneurons, focusing specifically on the induction and maintenance of LTP, and what the functional impact of persistent changes in efficacy at MF – interneuron synapses might be on the emergent properties of the inhibitory network dynamics in area CA3. PMID:21093459

  1. Nogo Receptor Signaling Restricts Adult Neural Plasticity by Limiting Synaptic AMPA Receptor Delivery

    PubMed Central

    Jitsuki, Susumu; Nakajima, Waki; Takemoto, Kiwamu; Sano, Akane; Tada, Hirobumi; Takahashi-Jitsuki, Aoi; Takahashi, Takuya

    2016-01-01

    Experience-dependent plasticity is limited in the adult brain, and its molecular and cellular mechanisms are poorly understood. Removal of the myelin-inhibiting signaling protein, Nogo receptor (NgR1), restores adult neural plasticity. Here we found that, in NgR1-deficient mice, whisker experience-driven synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) insertion in the barrel cortex, which is normally complete by 2 weeks after birth, lasts into adulthood. In vivo live imaging by two-photon microscopy revealed more AMPAR on the surface of spines in the adult barrel cortex of NgR1-deficient than on those of wild-type (WT) mice. Furthermore, we observed that whisker stimulation produced new spines in the adult barrel cortex of mutant but not WT mice, and that the newly synthesized spines contained surface AMPAR. These results suggest that Nogo signaling limits plasticity by restricting synaptic AMPAR delivery in coordination with anatomical plasticity. PMID:26472557

  2. PLPP/CIN regulates bidirectional synaptic plasticity via GluN2A interaction with postsynaptic proteins

    PubMed Central

    Kim, Ji-Eun; Kim, Yeon-Joo; Lee, Duk-Shin; Kim, Ji Yang; Ko, Ah-Reum; Hyun, Hye-Won; Kim, Min Ju; Kang, Tae-Cheon

    2016-01-01

    Dendritic spines are dynamic structures whose efficacies and morphologies are modulated by activity-dependent synaptic plasticity. The actin cytoskeleton plays an important role in stabilization and structural modification of spines. However, the regulatory mechanism by which it alters the plasticity threshold remains elusive. Here, we demonstrate the role of pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN), one of the cofilin-mediated F-actin regulators, in modulating synaptic plasticity in vivo. PLPP/CIN transgenic (Tg) mice had immature spines with small heads, while PLPP/CIN knockout (KO) mice had gigantic spines. Furthermore, PLPP/CIN Tg mice exhibited enhanced synaptic plasticity, but KO mice showed abnormal synaptic plasticity. The PLPP/CIN-induced alterations in synaptic plasticity were consistent with the acquisition and the recall capacity of spatial learning. PLPP/CIN also enhanced N-methyl-D-aspartate receptor (GluN) functionality by regulating the coupling of GluN2A with interacting proteins, particularly postsynaptic density-95 (PSD95). Therefore, these results suggest that PLPP/CIN may be an important factor for regulating the plasticity threshold. PMID:27212638

  3. Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

    PubMed

    Zhu, Li Qiang; Wan, Chang Jin; Gao, Ping Qi; Liu, Yang Hui; Xiao, Hui; Ye, Ji Chun; Wan, Qing

    2016-08-24

    Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton-gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing. PMID:27471861

  4. Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer's model.

    PubMed

    Xu, Zhi-Peng; Li, Li; Bao, Jian; Wang, Zhi-Hao; Zeng, Juan; Liu, En-Jie; Li, Xiao-Guang; Huang, Rong-Xi; Gao, Di; Li, Meng-Zhu; Zhang, Yao; Liu, Gong-Ping; Wang, Jian-Zhi

    2014-01-01

    Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy. PMID:25268773

  5. Magnesium Protects Cognitive Functions and Synaptic Plasticity in Streptozotocin-Induced Sporadic Alzheimer’s Model

    PubMed Central

    Bao, Jian; Wang, Zhi-Hao; Zeng, Juan; Liu, En-Jie; Li, Xiao-Guang; Huang, Rong-Xi; Gao, Di; Li, Meng-Zhu; Zhang, Yao; Liu, Gong-Ping; Wang, Jian-Zhi

    2014-01-01

    Alzheimer’s disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy. PMID:25268773

  6. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease

    PubMed Central

    D'Arcangelo, G.; Grossi, D.; Racaniello, M.; Cardinale, A.; Zaratti, A.; Rufini, S.; Cutarelli, A.; Tancredi, V.; Merlo, D.; Frank, C.

    2016-01-01

    Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia. PMID:26885401

  7. Applicability of the coefficient of variation method for analyzing synaptic plasticity.

    PubMed Central

    Faber, D S; Korn, H

    1991-01-01

    The classical coefficient of variation method for "quantal" analysis of synaptic responses allows unambiguous identification of pre- and postsynaptic loci underlying synaptic plasticity only when extensive simplifying restrictions are made. They include invariance of quantal parameters and the assumption that a single afferent produces the evoked potentials or currents. More general theoretical formulations and simulations demonstrate that the standard criteria do not always provide useful guidelines because when the other sources of physiological variance are included, putative pre- and postsynaptic domains may overlap. For example, data typically interpreted as indicating modifications at both sites can be due to a mechanism localized to only one of the two, if parameter variances are taken into consideration in the case of a single input cell, or if there are multiple inputs and the stimulus does not activate all of them reliably. With this perspective, other physiologically realistic hypotheses relevant to the expression of synaptic plasticity, such as that during long-term potentiation, can be envisioned. PMID:1684726

  8. Mind Bomb-2 Regulates Hippocampus-dependent Memory Formation and Synaptic Plasticity.

    PubMed

    Kim, Somi; Kim, TaeHyun; Lee, Hye-Ryeon; Kong, Young-Yun; Kaang, Bong-Kiun

    2015-11-01

    Notch signaling is a key regulator of neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-2 (Mib2) is an essential positive regulator of the Notch pathway, which acts in the Notch signal-sending cells. Therefore, genetic deletion of Mib2 in the mouse brain might help understand Notch signaling-mediated cell-cell interactions between neurons and their physiological function. Here we show that deletion of Mib2 in the mouse brain results in impaired hippocampal spatial memory and contextual fear memory. Accordingly, we found impaired hippocampal synaptic plasticity in Mib2 knock-out (KO) mice; however, basal synaptic transmission did not change at the Schaffer collateral-CA1 synapses. Using western blot analysis, we found that the level of cleaved Notch1 was lower in Mib2 KO mice than in wild type (WT) littermates after mild foot shock. Taken together, these data suggest that Mib2 plays a critical role in synaptic plasticity and spatial memory through the Notch signaling pathway.

  9. UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.

    PubMed

    Sun, Jiandong; Zhu, Guoqi; Liu, Yan; Standley, Steve; Ji, Angela; Tunuguntla, Rashmi; Wang, Yubin; Claus, Chad; Luo, Yun; Baudry, Michel; Bi, Xiaoning

    2015-07-21

    Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca(2+) sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function. PMID:26166566

  10. Mind Bomb-2 Regulates Hippocampus-dependent Memory Formation and Synaptic Plasticity

    PubMed Central

    Kim, Somi; Kim, TaeHyun; Lee, Hye-Ryeon; Kong, Young-Yun

    2015-01-01

    Notch signaling is a key regulator of neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-2 (Mib2) is an essential positive regulator of the Notch pathway, which acts in the Notch signal-sending cells. Therefore, genetic deletion of Mib2 in the mouse brain might help understand Notch signaling-mediated cell-cell interactions between neurons and their physiological function. Here we show that deletion of Mib2 in the mouse brain results in impaired hippocampal spatial memory and contextual fear memory. Accordingly, we found impaired hippocampal synaptic plasticity in Mib2 knock-out (KO) mice; however, basal synaptic transmission did not change at the Schaffer collateral-CA1 synapses. Using western blot analysis, we found that the level of cleaved Notch1 was lower in Mib2 KO mice than in wild type (WT) littermates after mild foot shock. Taken together, these data suggest that Mib2 plays a critical role in synaptic plasticity and spatial memory through the Notch signaling pathway. PMID:26557018

  11. Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease.

    PubMed

    Cavallucci, Virve; Berretta, Nicola; Nobili, Annalisa; Nisticò, Robert; Mercuri, Nicola B; D'Amelio, Marcello

    2013-09-01

    Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer's type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer's disease.

  12. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation.

    PubMed

    Hawasli, Ammar H; Benavides, David R; Nguyen, Chan; Kansy, Janice W; Hayashi, Kanehiro; Chambon, Pierre; Greengard, Paul; Powell, Craig M; Cooper, Donald C; Bibb, James A

    2007-07-01

    Learning is accompanied by modulation of postsynaptic signal transduction pathways in neurons. Although the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) has been implicated in cognitive disorders, its role in learning has been obscured by the perinatal lethality of constitutive knockout mice. Here we report that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents. Enhanced synaptic plasticity in Cdk5 knockout mice was attributed to reduced NR2B degradation, which caused elevations in total, surface and synaptic NR2B subunit levels and current through NR2B-containing NMDARs. Cdk5 facilitated the degradation of NR2B by directly interacting with both it and its protease, calpain. These findings reveal a previously unknown mechanism by which Cdk5 facilitates calpain-mediated proteolysis of NR2B and may control synaptic plasticity and learning.

  13. Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders

    PubMed Central

    Klein, Matthew E.; Monday, Hannah; Jordan, Bryen A.

    2016-01-01

    Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders. PMID:26904297

  14. Short-Term Vocational Evaluation.

    ERIC Educational Resources Information Center

    Botterbusch, Karl F.

    This guide is intended to assist vocational rehabilitation counselors in planning and conducting short-term vocational evaluations of clients. The first section discusses the elements that must be included in a comprehensive vocational evaluation. Next, strategies for conducting a vocational evaluation are explained. The next section, a case study…

  15. More than synaptic plasticity: Role of nonsynaptic plasticity in learning and memory

    PubMed Central

    Mozzachiodi, Riccardo; Byrne, John H.

    2009-01-01

    Decades of research on the cellular mechanisms of memory have led to the widely-held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories may also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes may function as part of the engram itself, they may also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage. PMID:19889466

  16. Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex.

    PubMed

    Urban, Kimberly R; Li, Yan-Chun; Gao, Wen-Jun

    2013-03-01

    Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning.

  17. Neuroligin 1 regulates spines and synaptic plasticity via LIMK1/cofilin-mediated actin reorganization

    PubMed Central

    Liu, An; Zhou, Zikai; Dang, Rui; Zhu, Yuehua; Qi, Junxia; He, Guiqin; Leung, Celeste; Pak, Daniel

    2016-01-01

    Neuroligin (NLG) 1 is important for synapse development and function, but the underlying mechanisms remain unclear. It is known that at least some aspects of NLG1 function are independent of the presynaptic neurexin, suggesting that the C-terminal domain (CTD) of NLG1 may be sufficient for synaptic regulation. In addition, NLG1 is subjected to activity-dependent proteolytic cleavage, generating a cytosolic CTD fragment, but the significance of this process remains unknown. In this study, we show that the CTD of NLG1 is sufficient to (a) enhance spine and synapse number, (b) modulate synaptic plasticity, and (c) exert these effects via its interaction with spine-associated Rap guanosine triphosphatase–activating protein and subsequent activation of LIM-domain protein kinase 1/cofilin–mediated actin reorganization. Our results provide a novel postsynaptic mechanism by which NLG1 regulates synapse development and function. PMID:26880202

  18. Neuroligin 1 regulates spines and synaptic plasticity via LIMK1/cofilin-mediated actin reorganization.

    PubMed

    Liu, An; Zhou, Zikai; Dang, Rui; Zhu, Yuehua; Qi, Junxia; He, Guiqin; Leung, Celeste; Pak, Daniel; Jia, Zhengping; Xie, Wei

    2016-02-15

    Neuroligin (NLG) 1 is important for synapse development and function, but the underlying mechanisms remain unclear. It is known that at least some aspects of NLG1 function are independent of the presynaptic neurexin, suggesting that the C-terminal domain (CTD) of NLG1 may be sufficient for synaptic regulation. In addition, NLG1 is subjected to activity-dependent proteolytic cleavage, generating a cytosolic CTD fragment, but the significance of this process remains unknown. In this study, we show that the CTD of NLG1 is sufficient to (a) enhance spine and synapse number, (b) modulate synaptic plasticity, and (c) exert these effects via its interaction with spine-associated Rap guanosine triphosphatase-activating protein and subsequent activation of LIM-domain protein kinase 1/cofilin-mediated actin reorganization. Our results provide a novel postsynaptic mechanism by which NLG1 regulates synapse development and function. PMID:26880202

  19. Exocytosis of gliotransmitters from cortical astrocytes: implications for synaptic plasticity and aging.

    PubMed

    Lalo, Ulyana; Rasooli-Nejad, Seyed; Pankratov, Yuriy

    2014-10-01

    Maintaining brain function during aging is very important for mental and physical health. Recent studies showed a crucial importance of communication between two major types of brain cells: neurons transmitting electrical signals, and glial cells, which maintain the well-being and function of neurons. Still, the study of age-related changes in neuron-glia signalling is far from complete. We have shown previously that cortical astrocytes are capable of releasing ATP by a quantal soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complex-dependent mechanism. Release of ATP from cortical astrocytes can be activated via various pathways, including direct UV-uncaging of intracellular Ca²⁺ or G-protein-coupled receptors. Importantly, release of both ATP and glutamate from neocortical astrocytes was not observed in brain slices of dominant-negative SNARE (dnSNARE) mice, expressing dnSNARE domain selectively in astrocytes. We also discovered that astrocyte-driven ATP can cause significant attenuation of synaptic inhibition in the pyramidal neurons via Ca²⁺-interaction between the neuronal ATP and γ-aminobutyric acid (GABA) receptors. Furthermore, we showed that astrocyte-derived ATP can facilitate the induction of long-term potentiation of synaptic plasticity in the neocortex. Our recent data have shown that an age-related decrease in the astroglial Ca²⁺ signalling can cause a substantial decrease in the exocytosis of gliotransmitters, in particular ATP. Age-related impairment of ATP release from cortical astrocytes can cause a decrease in the extent of astroglial modulation of synaptic transmission in the neocortex and can therefore contribute to the age-related impairment of synaptic plasticity and cognitive decline. Combined, our results strongly support the physiological relevance of glial exocytosis for glia-neuron communications and brain function. PMID:25233403

  20. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex

    PubMed Central

    Pankratov, Yuriy; Lalo, Ulyana

    2015-01-01

    Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying gliotransmission remain uncertain with exocytosis being the most intriguing and debated pathway. We demonstrate that astroglial α1-adrenoreceptors are very sensitive to noradrenaline (NA) and make a significant contribution to intracellular Ca2+-signaling in layer 2/3 neocortical astrocytes. We also show that astroglial α1-adrenoreceptors are prone to desensitization upon prolonged exposure to NA. We show that within neocortical slices, α-1adrenoreceptors can activate vesicular release of ATP and D-serine from cortical astrocytes which initiate a burst of ATP receptor-mediated currents in adjacent pyramidal neurons. These purinergic currents can be inhibited by intracellular perfusion of astrocytes with Tetanus Toxin light chain, verifying their origin via astroglial exocytosis. We show that α1 adrenoreceptor-activated release of gliotransmitters is important for the induction of synaptic plasticity in the neocortex:long-term potentiation (LTP) of neocortical excitatory synaptic potentials can be abolished by the selective α1-adrenoreceptor antagonist terazosin. We show that weak sub-threshold theta-burst stimulation (TBS) can induce LTP when astrocytes are additionally activated by 1 μM NA. This facilitation is dependent on the activation of neuronal ATP receptors and is abolished in neocortical slices from dn-SNARE mice which have impaired glial exocytosis. Importantly, facilitation of LTP by NA can be significantly reduced by perfusion of individual astrocytes with Tetanus Toxin. Our results strongly support the physiological importance of astroglial adrenergic signaling and exocytosis of gliotransmitters for modulation of synaptic transmission and plasticity. PMID:26136663

  1. PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling.

    PubMed

    Liu, Xingfeng; Huai, Jisen; Endle, Heiko; Schlüter, Leslie; Fan, Wei; Li, Yunbo; Richers, Sebastian; Yurugi, Hajime; Rajalingam, Krishnaraj; Ji, Haichao; Cheng, Hong; Rister, Benjamin; Horta, Guilherme; Baumgart, Jan; Berger, Hendrik; Laube, Gregor; Schmitt, Ulrich; Schmeisser, Michael J; Boeckers, Tobias M; Tenzer, Stefan; Vlachos, Andreas; Deller, Thomas; Nitsch, Robert; Vogt, Johannes

    2016-08-01

    Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/β1-integrin activation. PRG-1 deficiency reduces spine numbers and β1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of β1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation. PMID:27453502

  2. Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace

    PubMed Central

    Minatohara, Keiichiro; Akiyoshi, Mika; Okuno, Hiroyuki

    2016-01-01

    In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs) such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas. PMID:26778955

  3. The role of agrin in synaptic development, plasticity and signaling in the central nervous system.

    PubMed

    Daniels, Mathew P

    2012-11-01

    Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in the basal lamina of various tissues, whereas a transmembrane form is highly expressed in the brain. Expression in the brain is greatest during the period of synaptogenesis, but remains high in regions of the adult brain that show extensive synaptic plasticity. The well-established role of agrin in NMJ development and its presence in the brain elicited investigations of its possible role in synaptogenesis in the brain. Initial studies on the embryonic brain and neuronal cultures of agrin-null mice did not reveal any defects in synaptogenesis. However, subsequent studies in culture demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA. More recently, a substantial loss of excitatory synapses was found in the brains of transgenic adult mice that lacked agrin expression everywhere but in motor neurons. The mechanisms by which agrin influences synapse formation, maintenance and plasticity may include enhancement of excitatory synaptic signaling, activation of the "muscle-specific" receptor tyrosine kinase (MuSK) and positive regulation of dendritic filopodia. In this article I will review the evidence that agrin regulates synapse development, plasticity and signaling in the brain and discuss the evidence for the proposed mechanisms.

  4. Role of F3/contactin expression profile in synaptic plasticity and memory in aged mice.

    PubMed

    Puzzo, Daniela; Bizzoca, Antonella; Loreto, Carla; Guida, Chiara A; Gulisano, Walter; Frasca, Giuseppina; Bellomo, Maria; Castorina, Sergio; Gennarini, Gianfranco; Palmeri, Agostino

    2015-04-01

    We have recently shown that overexpression of the F3/contactin adhesive glycoprotein (also known as Contactin-1) promotes neurogenesis in adult hippocampus, which correlates with improved synaptic plasticity and memory. Because F3/contactin levels physiologically decrease with age, here, we aim at investigating whether its overexpression might counteract the cognitive decline in aged animals. For this we use 20- to 24-month-old TAG/F3 transgenic mice in which F3/contactin overexpression is driven by regulatory sequences from the gene encoding the transient axonal glycoprotein TAG-1 throughout development. We show that aged TAG/F3 mice display improved hippocampal long-term potentiation and memory compared with wild-type littermates. The same mice undergo a decrease of neuronal apoptosis at the hippocampal level, which correlated to a decrease of active caspase-3; by contrast, procaspase-3 and Bax as well as the anti-apoptotic and plasticity-related pathway BDNF/CREB/Bcl-2 were rather increased. Interestingly, amyloid-precursor protein processing was shifted toward sAPPα generation, with a decrease of sAPPβ and amyloid-beta levels. Our data confirm that F3/contactin plays a role in hippocampal synaptic plasticity and memory also in aged mice, suggesting that it acts on molecular pathways related to apoptosis and amyloid-beta production.

  5. Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule.

    PubMed

    Zhang, H; Etherington, L-A; Hafner, A-S; Belelli, D; Coussen, F; Delagrange, P; Chaouloff, F; Spedding, M; Lambert, J J; Choquet, D; Groc, L

    2013-04-01

    The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity. PMID:22733125

  6. Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

    PubMed

    Sagar, Vidya; Atluri, Venkata Subba Rao; Pilakka-Kanthikeel, Sudheesh; Nair, Madhavan

    2016-01-01

    The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression. In the same line, mild to severe neurological alterations are seen in at least 80 % autopsies of AIDS patients. Neurological illnesses weaken the connections between neurons causing significant altercations in synaptic plasticity. Synaptic plasticity alterations during HIV infection and recreational drug abuse are mediated by complex cellular phenomena involving changes in gene expression and subsequent loss of dendritic and spine morphology and physiology. New treatment strategies with ability to deliver drugs across blood-brain barrier (BBB) are being intensively investigated. In this context, magnetic nanoparticles (MNPs) based nanoformulations have shown significant potential for target specificity, drug delivery, drug release, and bioavailability of desired amount of drugs in non-invasive brain targeting. MNPs-based potential therapies to promote neuronal plasticity during HIV infection and recreational drug abuse are being developed. PMID:27216740

  7. The Role of Agrin in Synaptic Development, Plasticity and Signaling in the Central Nervous System

    PubMed Central

    Daniels, Mathew P.

    2012-01-01

    Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in the basal lamina of various tissues, whereas a transmembrane form is highly expressed in the brain. Expression in the brain is greatest during the period of synaptogenesis, but remains high in regions of the adult brain that show extensive synaptic plasticity. The well-established role of agrin in NMJ development and its presence in the brain elicited investigations of its possible role in synaptogenesis in the brain. Initial studies on the embryonic brain and neuronal cultures of agrin-null mice did not reveal any defects in synaptogenesis. However, subsequent studies in culture demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA. More recently, a substantial loss of excitatory synapses was found in the brains of transgenic adult mice that lacked agrin expression everywhere but in motor neurons. The mechanisms by which agrin influences synapse formation, maintenance and plasticity may include enhancement of excitatory synaptic signaling, activation of the “muscle-specific” receptor tyrosine kinase (MuSK) and positive regulation of dendritic filopodia. In this article I will review the evidence that agrin regulates synapse development, plasticity and signaling in the brain and discuss the evidence for the proposed mechanisms. PMID:22414531

  8. Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace.

    PubMed

    Minatohara, Keiichiro; Akiyoshi, Mika; Okuno, Hiroyuki

    2015-01-01

    In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs) such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas. PMID:26778955

  9. Discrete states of synaptic strength in a stochastic model of spike-timing-dependent plasticity.

    PubMed

    Elliott, Terry

    2010-01-01

    A stochastic model of spike-timing-dependent plasticity (STDP) postulates that single synapses presented with a single spike pair exhibit all-or-none quantal jumps in synaptic strength. The amplitudes of the jumps are independent of spiking timing, but their probabilities do depend on spiking timing. By making the amplitudes of both upward and downward transitions equal, synapses then occupy only a discrete set of states of synaptic strength. We explore the impact of a finite, discrete set of strength states on our model, finding three principal results. First, a finite set of strength states limits the capacity of a single synapse to express the standard, exponential STDP curve. We derive the expression for the expected change in synaptic strength in response to a standard, experimental spike pair protocol, finding a deviation from exponential behavior. We fit our prediction to recent data from single dendritic spine heads, finding results that are somewhat better than exponential fits. Second, we show that the fixed-point dynamics of our model regulate the upward and downward transition probabilities so that these are on average equal, leading to a uniform distribution of synaptic strength states. However, third, under long-term potentiation (LTP) and long-term depression (LTD) protocols, these probabilities are unequal, skewing the distribution away from uniformity. If the number of states of strength is at least of order 10, then we find that three effective states of synaptic strength appear, consistent with some experimental data on ternary-strength synapses. On this view, LTP and LTD protocols may therefore be saturating protocols.

  10. Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor

    PubMed Central

    Yang, Hongwei; Zhang, Jian; Breyer, Richard M.; Chen, Chu

    2008-01-01

    Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a presynaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation (LTP) at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that LTP was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio (PPR) in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function. PMID:19012750

  11. Unsupervised discrimination of patterns in spiking neural networks with excitatory and inhibitory synaptic plasticity

    PubMed Central

    Srinivasa, Narayan; Cho, Youngkwan

    2014-01-01

    A spiking neural network model is described for learning to discriminate among spatial patterns in an unsupervised manner. The network anatomy consists of source neurons that are activated by external inputs, a reservoir that resembles a generic cortical layer with an excitatory-inhibitory (EI) network and a sink layer of neurons for readout. Synaptic plasticity in the form of STDP is imposed on all the excitatory and inhibitory synapses at all times. While long-term excitatory STDP enables sparse and efficient learning of the salient features in inputs, inhibitory STDP enables this learning to be stable by establishing a balance between excitatory and inhibitory currents at each neuron in the network. The synaptic weights between source and reservoir neurons form a basis set for the input patterns. The neural trajectories generated in the reservoir due to input stimulation and lateral connections between reservoir neurons can be readout by the sink layer neurons. This activity is used for adaptation of synapses between reservoir and sink layer neurons. A new measure called the discriminability index (DI) is introduced to compute if the network can discriminate between old patterns already presented in an initial training session. The DI is also used to compute if the network adapts to new patterns without losing its ability to discriminate among old patterns. The final outcome is that the network is able to correctly discriminate between all patterns—both old and new. This result holds as long as inhibitory synapses employ STDP to continuously enable current balance in the network. The results suggest a possible direction for future investigation into how spiking neural networks could address the stability-plasticity question despite having continuous synaptic plasticity. PMID:25566045

  12. Unsupervised discrimination of patterns in spiking neural networks with excitatory and inhibitory synaptic plasticity.

    PubMed

    Srinivasa, Narayan; Cho, Youngkwan

    2014-01-01

    A spiking neural network model is described for learning to discriminate among spatial patterns in an unsupervised manner. The network anatomy consists of source neurons that are activated by external inputs, a reservoir that resembles a generic cortical layer with an excitatory-inhibitory (EI) network and a sink layer of neurons for readout. Synaptic plasticity in the form of STDP is imposed on all the excitatory and inhibitory synapses at all times. While long-term excitatory STDP enables sparse and efficient learning of the salient features in inputs, inhibitory STDP enables this learning to be stable by establishing a balance between excitatory and inhibitory currents at each neuron in the network. The synaptic weights between source and reservoir neurons form a basis set for the input patterns. The neural trajectories generated in the reservoir due to input stimulation and lateral connections between reservoir neurons can be readout by the sink layer neurons. This activity is used for adaptation of synapses between reservoir and sink layer neurons. A new measure called the discriminability index (DI) is introduced to compute if the network can discriminate between old patterns already presented in an initial training session. The DI is also used to compute if the network adapts to new patterns without losing its ability to discriminate among old patterns. The final outcome is that the network is able to correctly discriminate between all patterns-both old and new. This result holds as long as inhibitory synapses employ STDP to continuously enable current balance in the network. The results suggest a possible direction for future investigation into how spiking neural networks could address the stability-plasticity question despite having continuous synaptic plasticity.

  13. Proteasome Modulates Positive and Negative Translational Regulators in Long-Term Synaptic Plasticity

    PubMed Central

    Dong, Chenghai; Bach, Svitlana V.; Haynes, Kathryn A.

    2014-01-01

    Proteolysis by the ubiquitin-proteasome pathway appears to have a complex role in synaptic plasticity, but its various functions remain to be elucidated. Using late phase long-term potentiation (L-LTP) in the hippocampus of the mouse as a model for long-term synaptic plasticity, we previously showed that inhibition of the proteasome enhances induction but blocks maintenance of L-LTP. In this study, we investigated the possible mechanisms by which proteasome inhibition has opposite effects on L-LTP induction and maintenance. Our results show that inhibiting phosphatidyl inositol-3 kinase or blocking the interaction between eukaryotic initiation factors 4E (eIF4E) and 4G (eIF4G) reduces the enhancement of L-LTP induction brought about by proteasome inhibition suggesting interplay between proteolysis and the signaling pathway mediated by mammalian target of rapamycin (mTOR). Also, proteasome inhibition leads to accumulation of translational activators in the mTOR pathway such as eIF4E and eukaryotic elongation factor 1A (eEF1A) early during L-LTP causing increased induction. Furthermore, inhibition of the proteasome causes a buildup of translational repressors, such as polyadenylate-binding protein interacting protein 2 (Paip2) and eukaryotic initiation factor 4E-binding protein 2 (4E-BP2), during late stages of L-LTP contributing to the blockade of L-LTP maintenance. Thus, the proteasome plays a critical role in regulating protein synthesis during L-LTP by tightly controlling translation. Our results provide novel mechanistic insights into the interplay between protein degradation and protein synthesis in long-term synaptic plasticity. PMID:24573276

  14. Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

    PubMed Central

    Adasme, Tatiana; Haeger, Paola; Paula-Lima, Andrea C.; Espinoza, Italo; Casas-Alarcón, M. Mercedes; Carrasco, M. Angélica; Hidalgo, Cecilia

    2011-01-01

    Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation. PMID:21282625

  15. Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation.

    PubMed

    Adasme, Tatiana; Haeger, Paola; Paula-Lima, Andrea C; Espinoza, Italo; Casas-Alarcón, M Mercedes; Carrasco, M Angélica; Hidalgo, Cecilia

    2011-02-15

    Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation. PMID:21282625

  16. Parasagittal zones in the cerebellar cortex differ in excitability, information processing, and synaptic plasticity.

    PubMed

    Ebner, Timothy J; Wang, Xinming; Gao, Wangcai; Cramer, Samuel W; Chen, Gang

    2012-06-01

    At the molecular and circuitry levels, the cerebellum exhibits a striking parasagittal zonation as exemplified by the spatial distribution of molecules expressed on Purkinje cells and the topography of the afferent and efferent projections. The physiology and function of the zonation is less clear. Activity-dependent optical imaging has proven a useful tool to examine the physiological properties of the parasagittal zonation in the intact animal. Recent findings show that zebrin II-positive and zebrin II-negative zones differ markedly in their responses to parallel fiber inputs. These findings suggest that cerebellar cortical excitability, information processing, and synaptic plasticity depend on the intrinsic properties of different parasagittal zones. PMID:22249913

  17. Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

    PubMed

    Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

    2014-08-01

    An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

  18. Extracellular matrix molecules, their receptors, and secreted proteases in synaptic plasticity.

    PubMed

    Wlodarczyk, Jakub; Mukhina, Irina; Kaczmarek, Leszek; Dityatev, Alexander

    2011-11-01

    Neural cells secrete diverse molecules, which accumulate in the extracellular space and form the extracellular matrix (ECM). Interactions between cells and the ECM are well recognized to play the crucial role in cell migration and guidance of growing axons, whereas formation of mature neural ECM in the form of perineuronal nets is believed to restrict certain forms of developmental plasticity. On the other hand, major components of perineuronal nets and other ECM molecules support induction of functional plasticity, the most studied form of which is long-term potentiation. Here, we review the underlying mechanisms by which ECM molecules, their receptors and remodeling proteases regulate the induction and maintenance of synaptic modifications. In particular, we highlight that activity-dependent secretion and activation of proteases leads to a local cleavage of the ECM and release of signaling proteolytic fragments. These molecules regulate transmitter receptor trafficking, actin cytoskeleton, growth of dendritic spines, and formation of dendritic filopodia.

  19. Modeling the influence of short term depression in vesicle release and stochastic calcium channel gating on auditory nerve spontaneous firing statistics

    PubMed Central

    Moezzi, Bahar; Iannella, Nicolangelo; McDonnell, Mark D.

    2014-01-01

    We propose several modifications to an existing computational model of stochastic vesicle release in inner hair cell ribbon synapses, with the aim of producing simulated auditory nerve fiber spiking data that more closely matches empirical data. Specifically, we studied the inter-spike-interval (ISI) distribution, and long and short term ISI correlations in spontaneous spiking in post-synaptic auditory nerve fibers. We introduced short term plasticity to the pre-synaptic release probability, in a manner analogous to standard stochastic models of cortical short term synaptic depression. This modification resulted in a similar distribution of vesicle release intervals to that estimated from empirical data. We also introduced a biophysical stochastic model of calcium channel opening and closing, but showed that this model is insufficient for generating a match with empirically observed spike correlations. However, by combining a phenomenological model of channel noise and our short term depression model, we generated short and long term correlations in auditory nerve spontaneous activity that qualitatively match empirical data. PMID:25566047

  20. In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders.

    PubMed

    Pantazopoulos, Harry; Berretta, Sabina

    2016-01-01

    Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the "quadripartite" synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction.

  1. The effect of acute and chronic centrophenoxine treatment on the synaptic plasticity of old rats.

    PubMed

    Bertoni-Freddari, C; Giuli, C; Pieri, C

    1982-12-01

    The cerebellar glomerulus was studied by electron microscopic morphometry in female Wistar rats. Age-dependent alterations have been revealed from 3 to 28 mth of age, and the effect of centrophenoxine (CPH) was analyzed in two different patterns of administration. First, 27-mth-old rats were treated daily for 6 wk (acute treatment), and second, 18-mth-old rats were treated 3 times per week for 5 months (chronic treatment). The dose was 100 mg CPH/kg body weight, injected intraperitoneally. The surface density (SV), the numerical density (NV) and the average length (L) of the synaptic junctions were calculated from data obtained on ethanol-phosphotungstic acid stained ultrathin sections. An age-dependent reduction of SV and NV of the synaptic contact zones was found, and the L increased in the oldest animals. CPH-treatment resulted in a marked increase of SV in both types of application, whereas the other two parameters behaved differently in the two groups. The chronic treatment resulted in a significant slowing down of the decrease of NV, whereas L remained invariate. On the contrary, the acute treatment increased L but did not alter significantly NV. The results and the differences between the treatment types are discussed in terms of synaptic plasticity and are interpreted as different manifestations of the same reactive synaptogenetic process.

  2. The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity

    PubMed Central

    Smalheiser, Neil R.

    2014-01-01

    If mRNAs were the only RNAs made by a neuron, there would be a simple mapping of mRNAs to proteins. However, microRNAs and other non-coding RNAs (ncRNAs; endo-siRNAs, piRNAs, BC1, BC200, antisense and long ncRNAs, repeat-related transcripts, etc.) regulate mRNAs via effects on protein translation as well as transcriptional and epigenetic mechanisms. Not only are genes ON or OFF, but their ability to be translated can be turned ON or OFF at the level of synapses, supporting an enormous increase in information capacity. Here, I review evidence that ncRNAs are expressed pervasively within dendrites in mammalian brain; that some are activity-dependent and highly enriched near synapses; and that synaptic ncRNAs participate in plasticity responses including learning and memory. Ultimately, ncRNAs can be viewed as the post-it notes of the neuron. They have no literal meaning of their own, but derive their functions from where (and to what) they are stuck. This may explain, in part, why ncRNAs differ so dramatically from protein-coding genes, both in terms of the usual indicators of functionality and in terms of evolutionary constraints. ncRNAs do not appear to be direct mediators of synaptic transmission in the manner of neurotransmitters or receptors, yet they orchestrate synaptic plasticity—and may drive species-specific changes in cognition. PMID:25135965

  3. Synaptic plasticity in the medial superior olive of hearing, deaf, and cochlear-implanted cats.

    PubMed

    Tirko, Natasha N; Ryugo, David K

    2012-07-01

    The medial superior olive (MSO) is a key auditory brainstem structure that receives binaural inputs and is implicated in processing interaural time disparities used for sound localization. The deaf white cat, a proven model of congenital deafness, was used to examine how deafness and cochlear implantation affected the synaptic organization at this binaural center in the ascending auditory pathway. The patterns of axosomatic and axodendritic organization were determined for principal neurons from the MSO of hearing, deaf, and deaf cats with cochlear implants. The nature of the synapses was evaluated through electron microscopy, ultrastructure analysis of the synaptic vesicles, and immunohistochemistry. The results show that the proportion of inhibitory axosomatic terminals was significantly smaller in deaf animals when compared with hearing animals. However, after a period of electrical stimulation via cochlear implants the proportion of inhibitory inputs resembled that of hearing animals. Additionally, the excitatory axodendritic boutons of hearing cats were found to be significantly larger than those of deaf cats. Boutons of stimulated cats were significantly larger than the boutons in deaf cats, although not as large as in the hearing cats, indicating a partial recovery of excitatory inputs to MSO dendrites after stimulation. These results exemplify dynamic plasticity in the auditory brainstem and reveal that electrical stimulation through cochlear implants has a restorative effect on synaptic organization in the MSO. PMID:22237661

  4. In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders

    PubMed Central

    Pantazopoulos, Harry; Berretta, Sabina

    2016-01-01

    Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the “quadripartite” synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction. PMID:26839720

  5. Ribbon Synaptic Plasticity in Gravity Sensors of Rats Flown on Neurolab

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.; Varelas, Joseph

    2003-01-01

    Previous spaceflight experiments (Space Life Sciences-1 and -2 (SLS-1 and SLS-2)) first demonstrated the extraordinary ability of gravity sensor hair cells to change the number, kind, and distribution of connections (synapses) they make to other cells while in weightlessness. The number of synapses in hair cells in one part of the inner ear (the utricle) was markedly elevated on flight day 13 (FD13) of SLS-2. Unanswered questions, however, were whether these increases in synapses occur rapidly and whether they remain stable in weightlessness. The answers have implications for long-duration human space travel. If gravity sensors can adapt quickly, crews may be able to move easily between different gravity levels, since the sensors will adapt rapidly to weightlessness on the spacecraft and then back to Earth's gravity when the mission ends. This ability to adapt is also important for recovery from balance disorders. To further our understanding of this adaptive potential (a property called neuronal synaptic plasticity), the present Neurolab research was undertaken. Our experiment examined whether: (a) increases in synapses would remain stable throughout the flight, (b) changes in the number of synapses were uniform across different portions of the gravity sensors (the utricle and saccule), and (c) synaptic changes were similar for the different types of hair cells (Type I and Type II). Utricular and saccular maculae (the gravity-sensing portions of the inner ear) were collected in flight from rats on FD2 and FD14. Samples were also collected from control rats on the ground. Tissues were prepared for ultrastructural study. Hair cells and their ribbon synapses were examined in a transmission electron microscope. Synapses were counted in all hair cells in 50 consecutive sections that crossed the striolar zone. Results indicate that utricular hair cell synapses initially increased significantly in number in both types of hair cells by FD2. Counts declined by FD14, but

  6. Short-term memory traces for action bias in human reinforcement learning.

    PubMed

    Bogacz, Rafal; McClure, Samuel M; Li, Jian; Cohen, Jonathan D; Montague, P Read

    2007-06-11

    Recent experimental and theoretical work on reinforcement learning has shed light on the neural bases of learning from rewards and punishments. One fundamental problem in reinforcement learning is the credit assignment problem, or how to properly assign credit to actions that lead to reward or punishment following a delay. Temporal difference learning solves this problem, but its efficiency can be significantly improved by the addition of eligibility traces (ET). In essence, ETs function as decaying memories of previous choices that are used to scale synaptic weight changes. It has been shown in theoretical studies that ETs spanning a number of actions may improve the performance of reinforcement learning. However, it remains an open question whether including ETs that persist over sequences of actions allows reinforcement learning models to better fit empirical data regarding the behaviors of humans and other animals. Here, we report an experiment in which human subjects performed a sequential economic decision game in which the long-term optimal strategy differed from the strategy that leads to the greatest short-term return. We demonstrate that human subjects' performance in the task is significantly affected by the time between choices in a surprising and seemingly counterintuitive way. However, this behavior is naturally explained by a temporal difference learning model which includes ETs persisting across actions. Furthermore, we review recent findings that suggest that short-term synaptic plasticity in dopamine neurons may provide a realistic biophysical mechanism for producing ETs that persist on a timescale consistent with behavioral observations.

  7. Repetitive transcranial magnetic stimulation effectively facilitates spatial cognition and synaptic plasticity associated with increasing the levels of BDNF and synaptic proteins in Wistar rats.

    PubMed

    Shang, Yingchun; Wang, Xin; Shang, Xueliang; Zhang, Hui; Liu, Zhipeng; Yin, Tao; Zhang, Tao

    2016-10-01

    Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique, by which cognitive deficits can be alleviated. Furthermore, rTMS may facilitate learning and memory. However, its underlying mechanism is still little known. The aim of this study was to investigate if the facilitation of spatial cognition and synaptic plasticity, induced by rTMS, is regulated by enhancing pre- and postsynaptic proteins in normal rats. Morris water maze (MWM) test was performed to examine the spatial cognition. The synaptic plasticity, including long-term potentiation (LTP) and depotentiation (DEP), presynaptic plasticity paired-pulse facilitation (PPF), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured using in vivo electrophysiological techniques. The expressions of brain-derived neurotrophic factor (BDNF), presynaptic protein synaptophysin (SYP) and postsynaptic protein NR2B were measured by Western blot. Our data show that the spatial learning/memory and reversal learning/memory in rTMS rats were remarkably enhanced compared to that in the Sham group. Furthermore, LTP and DEP as well as PPF were effectively facilitated by 5Hz-rTMS. Additionally, the expressions of BDNF, SYP and NR2B were significantly increased via magnetic stimulation. The results suggest that rTMS considerably increases the expressions of BDNF, postsynaptic protein NR2B and presynaptic protein SYP, and thereby significantly enhances the synaptic plasticity and spatial cognition in normal animals. PMID:27555233

  8. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring.

    PubMed

    Stephan, Klaas E; Friston, Karl J; Frith, Chris D

    2009-05-01

    Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia. PMID:19155345

  9. Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring

    PubMed Central

    Stephan, Klaas E.; Friston, Karl J.; Frith, Chris D.

    2009-01-01

    Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia. PMID:19155345

  10. The nitric oxide-cyclic GMP pathway and synaptic plasticity in the rat superior cervical ganglion.

    PubMed Central

    Southam, E.; Charles, S. L.; Garthwaite, J.

    1996-01-01

    1. We have investigated the possibility that nitric oxide (NO) and soluble guanylyl cyclase, an enzyme that synthesizes guanosine 3':5'-cyclic monophosphate (cyclic GMP) in response to NO, contributes to plasticity of synaptic transmission in the rat isolated superior cervical ganglion (SCG). 2. Exposure of ganglia to the NO donor, nitroprusside, caused a concentration-dependent accumulation of cyclic GMP which was augmented in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. The compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, completely blocked this cyclic GMP response. 3. As assessed by extracellular recording, nitroprusside (100 microM) and another NO donor, S-nitrosoglutathione (30 microM) increased the efficacy of ganglionic synaptic transmission in response to electrical stimulation of the preganglionic nerve, an effect that was reversible and which could be replicated by the cyclic GMP analogue, 8-bromo-cyclic GMP. Ganglionic depolarizations resulting from stimulation of nicotinic receptors with carbachol were not increased by nitroprusside. The potentiating actions of the NO donors on synaptic transmission, but not that of 8-bromo-cyclic GMP, were inhibited by ODQ. 4. Brief tetanic stimulation of the preganglionic nerve resulted in a long-term potentiation (LTP) of synaptic transmission that was unaffected by ODQ, either in the absence or presence of the NO synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 100 microM). A lack of influence of L-NOARG was confirmed in intracellular recordings of LTP of the excitatory postsynaptic potential. Furthermore, under conditions where tetanically-induced LTP was saturated, nitroprusside was still able to potentiate synaptic transmission, as judged from extracellular recording. 5. We conclude that NO is capable of potentiating ganglionic neurotransmission and this effect is mediated through the stimulation of soluble guanylyl

  11. Repetitive transcranial magnetic stimulation (rTMS) influences spatial cognition and modulates hippocampal structural synaptic plasticity in aging mice.

    PubMed

    Ma, Jun; Zhang, Zhanchi; Kang, Lin; Geng, Dandan; Wang, Yanyong; Wang, Mingwei; Cui, Huixian

    2014-10-01

    Normal aging is characteristic with the gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in the hippocampus. Repetitive transcranial magnetic stimulation (rTMS) has developed into a novel neurological and psychiatric tool that can be used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency rTMS (≤1Hz) affects synaptic plasticity in rats with vascular dementia (VaD), and it ameliorates the spatial cognitive ability in mice with Aβ1-42-mediated memory deficits, but there are little concerns about the effects of rTMS on normal aging related cognition and synaptic plasticity changes. Thus, the current study investigated the effects of rTMS on spatial memory behavior, neuron and synapse morphology in the hippocampus, and synaptic protein markers and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) in normal aging mice, to illustrate the mechanisms of rTMS in regulating cognitive capacity. Relative to adult animals, aging caused hippocampal-dependent cognitive impairment, simultaneously inhibited the activation of the BDNF-TrkB signaling pathway, reduced the transcription and expression of synaptic protein markers: synaptophysin (SYN), growth associated protein 43 (GAP43) and post-synaptic density protein 95 (PSD95), as well as decreased synapse density and PSD (post-synaptic density) thickness. Interestingly, rTMS with low intensity (110% average resting motor threshold intensity, 1Hz, LIMS) triggered the activation of BDNF and TrkB, upregulated the level of synaptic protein markers, and increased synapse density and thickened PSD, and further reversed the spatial cognition dysfunction in aging mice. Conversely, high-intensity magnetic stimulation (150% average resting motor threshold intensity, 1Hz, HIMS) appeared to be detrimental, inducing thinning of PSDs, disordered synaptic structure, and a large number of

  12. Spike Timing Regulation on the Millisecond Scale by Distributed Synaptic Plasticity at the Cerebellum Input Stage: A Simulation Study

    PubMed Central

    Garrido, Jesús A.; Ros, Eduardo; D’Angelo, Egidio

    2013-01-01

    The way long-term synaptic plasticity regulates neuronal spike patterns is not completely understood. This issue is especially relevant for the cerebellum, which is endowed with several forms of long-term synaptic plasticity and has been predicted to operate as a timing and a learning machine. Here we have used a computational model to simulate the impact of multiple distributed synaptic weights in the cerebellar granular-layer network. In response to mossy fiber (MF) bursts, synaptic weights at multiple connections played a crucial role to regulate spike number and positioning in granule cells. The weight at MF to granule cell synapses regulated the delay of the first spike and the weight at MF and parallel fiber to Golgi cell synapses regulated the duration of the time-window during which the first-spike could be emitted. Moreover, the weights of synapses controlling Golgi cell activation regulated the intensity of granule cell inhibition and therefore the number of spikes that could be emitted. First-spike timing was regulated with millisecond precision and the number of spikes ranged from zero to three. Interestingly, different combinations of synaptic weights optimized either first-spike timing precision or spike number, efficiently controlling transmission and filtering properties. These results predict that distributed synaptic plasticity regulates the emission of quasi-digital spike patterns on the millisecond time-scale and allows the cerebellar granular layer to flexibly control burst transmission along the MF pathway. PMID:23720626

  13. Histone acetylation in the olfactory bulb of young rats facilitates aversive olfactory learning and synaptic plasticity.

    PubMed

    Wang, Y-J; Okutani, F; Murata, Y; Taniguchi, M; Namba, T; Kaba, H

    2013-03-01

    Epigenetic mechanisms play an important role in memory formation and synaptic plasticity. Specifically, histone-associated heterochromatin undergoes changes in structure during the early stages of long-term memory formation. In keeping with the classical conditioning paradigm, young rats have been shown to exhibit aversion to an odor stimulus initially presented during foot shock. We previously showed that synaptic plasticity at the dendrodendritic synapses between mitral and granule cells in the olfactory bulb (OB) underlies this aversive olfactory learning. However, the epigenetic mechanisms involved are not well characterized. Therefore, we examined whether intrabulbar infusion of trichostatin A (TSA), a histone deacetylase inhibitor, facilitates olfactory learning in young rats. TSA infusion during odor-shock training enhanced a conditioned odor aversion in a dose-dependent manner and prolonged the learned aversion. Western blot and immunohistochemical analyses showed that the level of histone H4 acetylation significantly increased until 4 h after odor-shock training in both mitral and granule cells in the OB, whereas histone H3 acetylation returned to the control level at 2 h after the training. We also obtained evidence that TSA infusion elevated acetylation of histone H4 or H3. Furthermore, in vitro electrophysiological analysis using slices of the OB revealed that application of TSA significantly enhanced the long-term potentiation induced in synaptic transmission from mitral to granule cells at dendrodendritic synapses. Taken together, these results provide evidence that histone H4 and H3 acetylation in the OB is an epigenetic mechanism associated with aversive olfactory learning in young rats.

  14. BDNF Interacts with Endocannabinoids to Regulate Cocaine-Induced Synaptic Plasticity in Mouse Midbrain Dopamine Neurons

    PubMed Central

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB1 receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  15. BDNF interacts with endocannabinoids to regulate cocaine-induced synaptic plasticity in mouse midbrain dopamine neurons.

    PubMed

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping; Liu, Qing-song

    2015-03-11

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB₁ receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  16. Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity.

    PubMed

    Lochner, J E; Spangler, E; Chavarha, M; Jacobs, C; McAllister, K; Schuttner, L C; Scalettar, B A

    2008-09-01

    Recent data suggest that tissue plasminogen activator (tPA) influences long-term plasticity at hippocampal synapses by converting plasminogen into plasmin, which then generates mature brain-derived neurotrophic factor (mBDNF) from its precursor, proBDNF. Motivated by this hypothesis, we used fluorescent chimeras, expressed in hippocampal neurons, to elucidate (1) mechanisms underlying plasminogen secretion from hippocampal neurons, (2) if tPA, plasminogen, and proBDNF are copackaged and cotransported in hippocampal neurons, especially within dendritic spines, and (3) mechanisms mediating the transport of these neuromodulators to sites of release. We find that plasminogen chimeras traffic through the regulated secretory pathway of hippocampal neurons in dense-core granules (DCGs) and that tPA, plasminogen, and proBDNF chimeras are extensively copackaged in DCGs throughout hippocampal neurons. We also find that 80% of spines that contain DCGs contain chimeras of these neuromodulators in the same DCG. Finally, we demonstrate, for the first time, that neuromodulators undergo cotransport along dendrites in rapidly mobile DCGs, indicating that neuromodulators can be efficiently recruited into active spines. These results support the hypothesis that tPA mediates synaptic activation of BDNF by demonstrating that tPA, plasminogen, and proBDNF colocalize in DCGs in spines, where these neuromodulators can undergo activity-dependent release and then interact and/or mediate changes that influence synaptic efficacy. The results also raise the possibility that frequency-dependent changes in extents of neuromodulator release from DCGs influence the direction of plasticity at hippocampal synapses by altering the relative proportions of two proteins, mBDNF and proBDNF, that exert opposing effects on synaptic efficacy.

  17. Impaired hippocampal synaptic plasticity and NR2A/2B expression ratio in remifentanil withdrawal rats.

    PubMed

    Wang, Yi-Yi; Liu, Shichang; Zhang, Nan; Yang, Jing; Zhang, Yinguo

    2016-03-01

    Remifentanil is a kind of synthetic opioid which has gained wide clinical acceptance by anesthesiologists. In this study, we attempted to test whether withdrawal effects on learning mechanisms can be triggered by repeated low-dose remifentanil treatment. Male Sprague-Dawley (SD) rats were subjected to remifentanil (50μg/kgs.c.) twice per day at 12h intervals for 15 days. When the animals of remifentanil group were withdrawn from remifentanil at 10h after the last injection, changes in open field test, Morris water maze test (MWM) and synaptic efficacy were examined in each group. We demonstrated that repeated exposure to 50μg/kg remifentanil produced enhanced locomotor activity indicating that a remifentanil addiction animal model in rats was established. MWM results showed that exposure to remifentanil had no influence on the spatial cognition. After withdrawal of remifentanil rats showed impaired spatial cognition. In electrophysiology test, remifentanil group rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Immunohistochemistry results demonstrated increased NR2A/NR2B ratio that should be included depression of LTP. In the whole-cell patch-clamp recording, after elimination from remifentanil incubation, mEPSC frequency was down regulated in hippocampal CA1 neurons, indicating that basal synaptic transmission were affected by remifentanil withdrawal. Taken together, the current findings demonstrate that the remifentanil withdrawn rats exhibit obvious impairment of hippocampus-dependent memory and synaptic plasticity. Increased hippocampal NR2A/NR2B expression ratio and the changes of basal synaptic transmission may participate in the impairment of LTP. PMID:26777139

  18. Loss of Catecholaminergic Neuromodulation of Persistent Forms of Hippocampal Synaptic Plasticity with Increasing Age

    PubMed Central

    Twarkowski, Hannah; Manahan-Vaughan, Denise

    2016-01-01

    Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24 h), and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP) and long-term depression (LTD), but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become apparent in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states. Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2–4 month old) and middle-aged (8–14 month old) rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2 h could be strengthened into persistent (>24 h) LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  19. Translational control by eIF2α kinases in long-lasting synaptic plasticity and long-term memory.

    PubMed

    Trinh, Mimi A; Klann, Eric

    2013-10-01

    Although the requirement for new protein synthesis in synaptic plasticity and memory has been well established, recent genetic, molecular, electrophysiological, and pharmacological studies have broadened our understanding of the translational control mechanisms that are involved in these processes. One of the critical translational control points mediating general and gene-specific translation depends on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by four regulatory kinases. Here, we review the literature highlighting the important role for proper translational control via regulation of eIF2α phosphorylation by its kinases in long-lasting synaptic plasticity and long-term memory.

  20. Synaptic plasticity and calcium signaling in Purkinje cells of the central cerebellar lobes of mormyrid fish.

    PubMed

    Han, Victor Z; Zhang, Yueping; Bell, Curtis C; Hansel, Christian

    2007-12-01

    Climbing fiber (CF)-evoked calcium transients play a key role in plasticity at parallel fiber (PF) to Purkinje cell synapses in the mammalian cerebellum. Whereas PF activation alone causes long-term potentiation (LTP), coactivation of the heterosynaptic CF input, which evokes large dendritic calcium transients, induces long-term depression (LTD). This unique type of heterosynaptic interaction is a hallmark feature of synaptic plasticity in mammalian Purkinje cells. Purkinje cells in the cerebellum of mormyrid electric fish are characterized by a different architecture of their dendritic trees and by a more pronounced separation of CF and PF synaptic contact sites. We therefore examined the conditions for bidirectional plasticity at PF synapses onto Purkinje cells in the mormyrid cerebellum in vitro. PF stimulation at elevated frequencies induces LTP, whereas LTD results from PF stimulation at enhanced intensities and depends on dendritic calcium influx and metabotropic glutamate receptor type 1 activation. LTD can also be observed after pairing of low intensity PF stimulation with CF stimulation. Using a combination of whole-cell patch-clamp recordings and fluorometric calcium imaging, we characterized calcium transients in Purkinje cell dendrites. CF activation elicits calcium transients not only within the CF input territory (smooth proximal dendrites) but also within the PF input territory (spiny palisade dendrites). Paired PF and CF activation elicits larger calcium transients than stimulation of either input alone. A major source for dendritic calcium signaling is provided by P/Q-type calcium channels. Our data show that despite the spatial separation between the two inputs CF activity facilitates LTD induction at PF synapses.

  1. BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment.

    PubMed

    Novkovic, Tanja; Mittmann, Thomas; Manahan-Vaughan, Denise

    2015-01-01

    Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain-derived neurotrophic factor (BDNF) supports hippocampal long-term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus-dependent learning that occurs following EE. In the absence of EE, LTP elicited by high-frequency stimulation was equivalent in wildtype mice and heterozygous BDNF(+/-) siblings. LTP elicited by theta-burst stimulation in BDNF(+/-) mice was less than in wildtypes. Long-term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF(+/-) mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE.

  2. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    PubMed

    Liu, Zhigang; Patil, Ishan Y; Jiang, Tianyi; Sancheti, Harsh; Walsh, John P; Stiles, Bangyan L; Yin, Fei; Cadenas, Enrique

    2015-01-01

    High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  3. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

    PubMed Central

    Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.

    2016-01-01

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular

  4. Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity

    PubMed Central

    Kotilinek, Linda A.; Westerman, Marcus A.; Wang, Qinwen; Panizzon, Kimberly; Lim, Giselle P.; Simonyi, Agnes; Lesne, Sylvain; Falinska, Agnieszka; Younkin, Linda H.; Younkin, Steven G.; Rowan, Michael; Cleary, James; Wallis, Roi Ann; Sun, GraceY.; Cole, Greg; Frautschy, Sally; Anwyl, Roger; Ashe, Karen H.

    2008-01-01

    Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer’s disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-β protein (Aβ). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Aβ from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer’s disease: one, the selective lowering of Aβ42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer’s disease is a disorder of brain and synaptic function, the effects of NSAIDs on Aβ-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Aβ42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Aβ-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Aβ. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Aβ-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Aβ42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Aβ42 or the inflammatory cytokines, tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2

  5. Layer-specific cholinergic control of human and mouse cortical synaptic plasticity.

    PubMed

    Verhoog, Matthijs B; Obermayer, Joshua; Kortleven, Christian A; Wilbers, René; Wester, Jordi; Baayen, Johannes C; De Kock, Christiaan P J; Meredith, Rhiannon M; Mansvelder, Huibert D

    2016-01-01

    Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans. PMID:27604129

  6. Layer-specific cholinergic control of human and mouse cortical synaptic plasticity

    PubMed Central

    Verhoog, Matthijs B.; Obermayer, Joshua; Kortleven, Christian A.; Wilbers, René; Wester, Jordi; Baayen, Johannes C.; De Kock, Christiaan P. J.; Meredith, Rhiannon M.; Mansvelder, Huibert D.

    2016-01-01

    Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans. PMID:27604129

  7. No effect of genetic deletion of contactin-associated protein (CASPR) on axonal orientation and synaptic plasticity.

    PubMed

    Pillai, Anilkumar M; Garcia-Fresco, German P; Sousa, Aurea D; Dupree, Jeffrey L; Philpot, Benjamin D; Bhat, Manzoor A

    2007-08-15

    Myelinated axons are endowed with a specialized domain structure that is essential for saltatory action potential conduction. The paranodal domain contains the axoglial junctions and displays a unique ultrastructure that resembles the invertebrate septate junctions (SJs). Biochemical characterizations of the paranodal axoglial SJs have identified several molecular components that include Caspr and contactin (Cont) on the axonal side and neurofascin 155 kDa (NF155) isoform on the glial side. All these proteins are essential for the formation of the axoglial SJs. Based on the interactions between Caspr and Cont and their colocalization in the CA1 synaptic areas, it was proposed that the synaptic function of Cont requires Caspr. Here we have extended the phenotypic analysis of CASPR mutants to address further the role of Caspr at the axoglial SJs and also in axonal orientation and synaptic plasticity. We report that, in CASPR mutants, the smooth endoplasmic reticulum (SER) forms elongated membranous complexes that accumulate at the nodal/paranodal region and stretch into the juxtaparanodal region, a defect that is consistent with the paranodal disorganization. We show that the cerebellar microorganization is unaffected in CASPR mutants. We also demonstrate that Caspr function is not essential for normal CA1 synaptic transmission and plasticity. Taken together with previous findings, our results highlight that the Caspr/Cont complex is essential for the formation of axoglial SJs, whereas Cont may regulate axonal orientation and synaptic plasticity independent of its association with Caspr. PMID:17549747

  8. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury

    PubMed Central

    Stuck, Ellen D.; Irvine, Karen-Amanda; Bresnahan, Jacqueline C.

    2015-01-01

    Abstract Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity. PMID:26668821

  9. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

    PubMed

    Huie, J Russell; Stuck, Ellen D; Lee, Kuan H; Irvine, Karen-Amanda; Beattie, Michael S; Bresnahan, Jacqueline C; Grau, James W; Ferguson, Adam R

    2015-01-01

    Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.

  10. Role of Rho Kinase and Fasudil on Synaptic Plasticity in Multiple Sclerosis.

    PubMed

    Chen, Chan; Yu, Jie-Zhong; Zhang, Qiong; Zhao, Yong-Fei; Liu, Chun-Yun; Li, Yan-Hua; Yang, Wan-Fang; Ma, Cun-Gen; Xiao, Bao-Guo

    2015-12-01

    In addition to myelin loss and oligodendrocyte injury, axonal damage is a major cause of irreversible neurological disability in multiple sclerosis (MS). A series of studies have demonstrated that Rho kinase (ROCK) is involved in synaptic plasticity of neurons. Here, we found that ROCK activity in MS serum was elevated compared with serum from healthy controls. In experimental autoimmune encephalomyelitis (EAE), ROCK activity was also increased in serum, spleen, brain and spinal cord. Neuron injury with scratch and TNF-α stimulation induced the up-regulation of ROCK activity. When serum of MS patients was co-cultured with mouse cortical neurons in vitro, MS serum caused neurite shortening and reduction of cell viability, while the addition of Fasudil partially restored synaptic morphology of neurons, revealing that MS sera inhibited neurite outgrowth and synapse formation. The expression of synaptophysin was decreased in MS serum-neurons, and elevated in the presence of Fasudil. In contrast, the expression of phosphorylated collapsin response mediator protein-2 (CRMP-2) was elevated in MS serum-neurons and decreased in the presence of Fasudil. However, the addition of anti-ROCK I/II mixed antibodies in MS serum partially declined ROCK activity, but did not improve neurite outgrowth of neurons, revealing that Fasudil should prevent synaptic damage possibly through inhibiting intracellular ROCK activation mediated with MS serum. Our results indicate that axonal loss in MS may be related to increased ROCK activity. Fasudil could promote synaptogenesis and thus may contribute to preventing irreversible neurological disability associated with MS. PMID:26481340

  11. A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

    PubMed

    Pollak, Daniela D; Minh, Bui Quang; Cicvaric, Ana; Monje, Francisco J

    2014-11-01

    Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.

  12. Self healing of open circuit faults: With active re-configurability and mimicry of synaptic plasticity

    NASA Astrophysics Data System (ADS)

    Yaswant, Vaddi; Kumar, Amit; Sambandan, Sanjiv

    2016-07-01

    We discuss the self-repair of open faults in circuits using electrically conductive particles dispersed in an insulating fluid. The repair is triggered by the electric field developed across the open circuit in a current carrying interconnect and results in the formation of a bridge of particles across the gap. We illustrate and model the dynamics of the resistance of the self-healed route, Rb, in low field conditions. Furthermore, active control of Rb and active re-wiring are also demonstrated. Considering Rb to be akin to weights between nodes, the formation and re-wiring of routes and the control of Rb mimic synaptic plasticity in biological systems and open interesting possibilities for computing.

  13. Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala.

    PubMed

    Du, Jianyang; Reznikov, Leah R; Price, Margaret P; Zha, Xiang-ming; Lu, Yuan; Moninger, Thomas O; Wemmie, John A; Welsh, Michael J

    2014-06-17

    Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acid-sensing ion channels (ASICs), Na(+)- and Ca(2+)-permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/receptor pair critical for amygdala-dependent learning and memory.

  14. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol.

    PubMed

    Liu, Rong-Yu; Zhang, Yili; Baxter, Douglas A; Smolen, Paul; Cleary, Leonard J; Byrne, John H

    2013-04-17

    Mutations in the gene encoding CREB-binding protein (CBP) cause deficits in long-term plasticity, learning, and memory. Here, long-term synaptic facilitation (LTF) at Aplysia sensorimotor synapses in cell culture was used as a model system to investigate methods for overcoming deficits in LTF produced by a CBP knockdown. Injecting CBP-siRNA into individual sensory neurons reduced CBP levels and impaired LTF produced by a standard protocol of five 5-min pulses of serotonin (5-HT) delivered at 20 min interstimulus intervals. A computational model, which simulated molecular processes underlying LTF induction, predicted a rescue protocol of five pulses of 5-HT at non-uniform interstimulus intervals that overcame the consequences of reduced CBP and restored LTF. These results suggest that complementary empirical and computational studies can identify methods for ameliorating impairments of learning attributable to molecular lesions.

  15. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol.

    PubMed

    Liu, Rong-Yu; Zhang, Yili; Baxter, Douglas A; Smolen, Paul; Cleary, Leonard J; Byrne, John H

    2013-04-17

    Mutations in the gene encoding CREB-binding protein (CBP) cause deficits in long-term plasticity, learning, and memory. Here, long-term synaptic facilitation (LTF) at Aplysia sensorimotor synapses in cell culture was used as a model system to investigate methods for overcoming deficits in LTF produced by a CBP knockdown. Injecting CBP-siRNA into individual sensory neurons reduced CBP levels and impaired LTF produced by a standard protocol of five 5-min pulses of serotonin (5-HT) delivered at 20 min interstimulus intervals. A computational model, which simulated molecular processes underlying LTF induction, predicted a rescue protocol of five pulses of 5-HT at non-uniform interstimulus intervals that overcame the consequences of reduced CBP and restored LTF. These results suggest that complementary empirical and computational studies can identify methods for ameliorating impairments of learning attributable to molecular lesions. PMID:23595752

  16. Two Mutations Preventing PDZ-Protein Interactions of GluR1 Have Opposite Effects on Synaptic Plasticity

    ERIC Educational Resources Information Center

    Boehm, Jannic; Ehrlich, Ingrid; Hsieh, Helen; Malinow, Roberto

    2006-01-01

    The regulated trafficking of GluR1 contributes significantly to synaptic plasticity, but studies addressing the function of the GluR1 C-terminal PDZ-ligand domain in this process have produced conflicting results. Here, we resolve this conflict by showing that apparently similar C-terminal mutations of the GluR1 PDZ-ligand domain result in…

  17. Effects of developmental perfluorooctane sulfonate exposure on spatial learning and memory ability of rats and mechanism associated with synaptic plasticity.

    PubMed

    Wang, Yu; Liu, Wei; Zhang, Qian; Zhao, Huimin; Quan, Xie

    2015-02-01

    The present study aims to explore the effects of perfluorooctane sulfonate (PFOS) on cognitive function in developing rats and the underlying mechanism associated with synaptic plasticity. Pregnant Wistar rats were fed with 0, 5, and 15 mg/L of PFOS via drinking water during gestation and lactation. Offspring were exposed to PFOS on prenatal and/or postnatal days by cross-fostering. Spatial learning and memory abilities were tested from postnatal day (PND) 35. We also analyzed the expression pattern of the synaptic plasticity-related genes and proteins in the hippocampus on PND7 and PND35. Results revealed that PFOS exposure reduced the spatial learning and memory abilities of the offspring, particularly of those with prenatal exposure. Meanwhile, protein levels of growth-associated protein-43, neural cell adhesion molecule 1, nerve growth factor, and brain-derived neurotrophic factor decreased on PND35, which are involved in the formation of synaptic plasticity. In contrast, significant increase in gap-43, ncam1, and bdnf genes on the mRNA level was observed on PND7, possibly due to the post-transcriptional mechanism. Results of both behavioral effects and molecular endpoints suggested the high risk of prenatal PFOS exposure. The decline of spatial learning and memory abilities induced by developmental PFOS exposure was closely related to synaptic plasticity.

  18. Different Compartments of Apical CA1 Dendrites Have Different Plasticity Thresholds for Expressing Synaptic Tagging and Capture

    ERIC Educational Resources Information Center

    Sajikumar, Sreedharan; Korte, Martin

    2011-01-01

    The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal…

  19. The Roles of MAPK Cascades in Synaptic Plasticity and Memory in "Aplysia": Facilitatory Effects and Inhibitory Constraints

    ERIC Educational Resources Information Center

    Sharma, Shiv K.; Carew, Thomas J.

    2004-01-01

    Synaptic plasticity is thought to contribute to memory formation. Serotonin-induced facilitation of sensory-motor (SN-MN) synapses in "Aplysia" is an extensively studied cellular analog of memory for sensitization. Serotonin, a modulatory neurotransmitter, is released in the CNS during sensitization training, and induces three temporally and…

  20. The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory

    PubMed Central

    Szu, Jenny I.; Binder, Devin K.

    2016-01-01

    Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4-null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4-null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory. PMID:26941623

  1. Enhancing synaptic plasticity and cellular resilience to develop novel, improved treatments for mood disorders

    PubMed Central

    Quiroz, Jorge A.; Manji, Husseini K.

    2002-01-01

    There is mounting evidence that recurrent mood disorders - once considered “good prognosis diseases”- are, in fact, often very severe and life-threatening illnesses. Furthermore, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes ofglia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that mood disorders are associated with impairments of synaptic plasticity and cellular resilience. In this context, it is noteworthy that there is increasing preclinical evidence that antidepressants regulate the function of the glutamatergic system. Moreover, although clearly preliminary, the available clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) function has antidepressant effects. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressant agents. Antidepressants and mood stabilizers indirectly regulate a number of factors involved in cell survival pathways, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), the antiapoptotic protein bcl-2, and mitogen-activated protein (MAP) kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. There is much promise for the future development of treatments that more directly target molecules in critical CNS signaling pathways regulating synaptic plasticity and cellular resilience. These will represent improved long-term treatments for mood disorders. PMID:22034240

  2. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.

    PubMed

    Vaynman, Shoshanna; Ying, Zhe; Gomez-Pinilla, Fernando

    2004-11-01

    We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.

  3. Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

    PubMed

    Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

    2015-07-01

    Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

  4. Action potential-induced dendritic calcium dynamics correlated with synaptic plasticity in developing hippocampal pyramidal cells.

    PubMed

    Isomura, Y; Kato, N

    1999-10-01

    In hippocampal CA1 pyramidal cells, intracellular calcium increases are required for induction of long-term potentiation (LTP), an activity-dependent synaptic plasticity. LTP is known to develop in magnitude during the second and third postnatal weeks in the rats. Little is known, however, about development of intracellular calcium dynamics during the same postnatal weeks. We investigated postnatal development of intracellular calcium dynamics in the proximal apical dendrites of CA1 pyramidal cells by whole cell patch-clamp recordings and calcium imaging with the Ca(2+) indicator fura-2. Dendritic calcium increases induced by intrasomatically evoked action potentials were slight during the first postnatal week but gradually became robust 3 to 6-fold during the second and third postnatal weeks. These calcium increases were blocked by application of 250 microM CdCl(2), a nonspecific blocker for high-threshold voltage-dependent calcium channels (VDCCs). Under the voltage-clamp condition, both calcium currents and dendritic calcium accumulations induced by depolarization were larger at the late developmental stage (P15-18) than the early stage (P4-7), indicating developmental enhancement of calcium influx mediated by high-threshold VDCCs. Moreover, theta-burst stimulation (TBS), a protocol for LTP induction, induced large intracellular calcium increases at the late developmental stage, in synchrony with maturation of TBS-induced LTP. These results suggest that developmental enhancement of intracellular calcium increases induced by action potentials may underlie maturation of calcium-dependent functions such as synaptic plasticity in hippocampal neurons.

  5. Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice

    PubMed Central

    Pan, Wensen; Han, Shuo; Kang, Lin; Li, Sha; Du, Juan; Cui, Huixian

    2016-01-01

    The current study focused on how dihydrotestosterone (DHT) regulates synaptic plasticity in the hippocampus of mild cognitive impairment male senescence-accelerated mouse prone 8 (SAMP8) mice. Five-month-old SAMP8 mice were divided into the control, castrated and castrated-DHT groups, in which the mice were castrated and treated with physiological doses of DHT for a period of 2 months. To determine the regulatory mechanisms of DHT in the cognitive capacity, the effects of DHT on the morphology of the synapse and the expression of synaptic marker proteins in the hippocampus were investigated using immunohistochemistry, qPCR and western blot analysis. The results showed that the expression of cAMP-response element binding protein (CREB), postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and developmentally regulated brain protein (Drebrin) was reduced in the castrated group compared to the control group. However, DHT promoted the expression of CREB, PSD95, SYN and Drebrin in the hippocampus of the castrated-DHT group. Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer's disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer's dementia. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function. PMID:27588067

  6. Properties and plasticity of synaptic inputs to rat dorsal column neurones recorded in vitro.

    PubMed

    Nuñez, A; Buño, W

    2001-09-01

    dorsal column EPSPs. Depolarising current facilitated dorsal column EPSPs but not corticofugal EPSPs. 5. These results indicate that synaptic interactions include different forms of activity-dependent synaptic plasticity, with the participation of NMDA receptors and probably Ca(2+) inflow through voltage-gated channels. These complex synaptic interactions may represent the cellular substrate of the integrative function of the dorsal column nuclei observed in vivo.

  7. Long short-term memory.

    PubMed

    Hochreiter, S; Schmidhuber, J

    1997-11-15

    Learning to store information over extended time intervals by recurrent backpropagation takes a very long time, mostly because of insufficient, decaying error backflow. We briefly review Hochreiter's (1991) analysis of this problem, then address it by introducing a novel, efficient, gradient-based method called long short-term memory (LSTM). Truncating the gradient where this does not do harm, LSTM can learn to bridge minimal time lags in excess of 1000 discrete-time steps by enforcing constant error flow through constant error carousels within special units. Multiplicative gate units learn to open and close access to the constant error flow. LSTM is local in space and time; its computational complexity per time step and weight is O(1). Our experiments with artificial data involve local, distributed, real-valued, and noisy pattern representations. In comparisons with real-time recurrent learning, back propagation through time, recurrent cascade correlation, Elman nets, and neural sequence chunking, LSTM leads to many more successful runs, and learns much faster. LSTM also solves complex, artificial long-time-lag tasks that have never been solved by previous recurrent network algorithms.

  8. Onboard Short Term Plan Viewer

    NASA Technical Reports Server (NTRS)

    Hall, Tim; LeBlanc, Troy; Ulman, Brian; McDonald, Aaron; Gramm, Paul; Chang, Li-Min; Keerthi, Suman; Kivlovitz, Dov; Hadlock, Jason

    2011-01-01

    Onboard Short Term Plan Viewer (OSTPV) is a computer program for electronic display of mission plans and timelines, both aboard the International Space Station (ISS) and in ISS ground control stations located in several countries. OSTPV was specifically designed both (1) for use within the limited ISS computing environment and (2) to be compatible with computers used in ground control stations. OSTPV supplants a prior system in which, aboard the ISS, timelines were printed on paper and incorporated into files that also contained other paper documents. Hence, the introduction of OSTPV has both reduced the consumption of resources and saved time in updating plans and timelines. OSTPV accepts, as input, the mission timeline output of a legacy, print-oriented, UNIX-based program called "Consolidated Planning System" and converts the timeline information for display in an interactive, dynamic, Windows Web-based graphical user interface that is used by both the ISS crew and ground control teams in real time. OSTPV enables the ISS crew to electronically indicate execution of timeline steps, launch electronic procedures, and efficiently report to ground control teams on the statuses of ISS activities, all by use of laptop computers aboard the ISS.

  9. Testing synaptic plasticity in dynamic mate choice decisions: N-methyl D-aspartate receptor blockade disrupts female preference.

    PubMed

    Ramsey, Mary E; Vu, Wendy; Cummings, Molly E

    2014-06-22

    Social behaviours such as mate choice require context-specific responses, often with evolutionary consequences. Increasing evidence indicates that the behavioural plasticity associated with mate choice involves learning. For example, poeciliids show age-dependent changes in female preference functions and express synaptic-plasticity-associated molecular markers during mate choice. Here, we test whether social cognition is necessary for female preference behaviour by blocking the central player in synaptic plasticity, NMDAR (N-methyl d-aspartate receptor), in a poeciliid fish, Xiphophorus nigrensis. After subchronic exposure to NMDAR antagonist MK-801, female preference behaviours towards males were dramatically reduced. Overall activity levels were unaffected, but there was a directional shift from 'social' behaviours towards neutral activity. Multivariate gene expression patterns significantly discriminated between females with normal versus disrupted plasticity processes and correlated with preference behaviours-not general activity. Furthermore, molecular patterns support a distinction between 'preference' (e.g. neuroserpin, neuroligin-3, NMDAR) and 'sociality' (isotocin and vasotocin) gene clusters, highlighting a possible conservation between NMDAR disruption and nonapeptides in modulating behaviour. Our results suggest that mate preference may involve greater social memory processing than overall sociality, and that poeciliid preference functions integrate synaptic-plasticity-oriented 'preference' pathways with overall sociality to invoke dynamic, context-specific responses towards favoured males and away from unfavoured males.

  10. The biochemical basis of synaptic plasticity and neurocomputation: a new theory.

    PubMed

    Smythies, J

    1997-04-22

    The recent finding that dendritic spines (on which 90% of all excitatory synapses on pyramidal cells are formed) are not permanent structures but are continually being formed and adsorbed has implications for the present theoretical basis of neurocomputation, which is largely based on the concept of fixed nerve nets. This evidence would tend to support the recent theories of Edelman, Freeman, Globus, Pribram and others that neuronal networks in the brain operate mainly as nonlinear dynamic, chaotic systems. This paper presents a hypothesis of a possible neurochemical mechanism underlying this synaptic plasticity based on reactive oxygen species and toxic 0-semiquinones derived from catecholamines (i) by the enzyme prostaglandin H synthetase induced by glutamatergic NMDA receptor activation and (ii) by reactive nitrogen species derived from nitric oxide in a low ascorbate environment. A key factor in this neuromodulation may be the fact that catecholamines are potent antioxidants and free radical scavengers and are thus able to affect the redox mediated balance at the glutamate receptors between synapse formation and synapse removal that may be a key factor in neurocomputational plasticity. But catecholamines are also easily oxidized to neurotoxic 0-semiquinones and this may be relevant to the pathology of several diseases including schizophrenia. The relationship between dopamine release and positive reinforcement is relevant to this hypothesis.

  11. Visual recognition memory, manifest as long-term habituation, requires synaptic plasticity in V1

    PubMed Central

    Cooke, Sam F.; Komorowski, Robert W.; Kaplan, Eitan S.; Gavornik, Jeffrey P.; Bear, Mark F.

    2015-01-01

    Familiarity with stimuli that bring neither reward nor punishment, manifested through behavioural habituation, enables organisms to detect novelty and devote cognition to important elements of the environment. Here we describe in mice a form of long-term behavioural habituation to visual grating stimuli that is selective for stimulus orientation. Orientation-selective habituation (OSH) can be observed both in exploratory behaviour in an open arena, and in a stereotyped motor response to visual stimuli in head-restrained mice. We show that the latter behavioural response, termed a vidget, requires V1. Parallel electrophysiological recordings in V1 reveal that plasticity, in the form of stimulus-selective response potentiation (SRP), occurs in layer 4 of V1 as OSH develops. Local manipulations of V1 that prevent and reverse electrophysiological modifications likewise prevent and reverse memory demonstrated behaviourally. These findings suggest that a form of long-term visual recognition memory is stored via synaptic plasticity in primary sensory cortex. PMID:25599221

  12. Ternary Synaptic Plasticity Arising from Memdiode Behavior of TiOx Single Nanowire

    NASA Astrophysics Data System (ADS)

    Hong, Deshun; Chen, Yuansha; Sun, Jirong; Shen, Baogen; Group 3 of Magnetism Laboratory, Beijing National Laboratory for Condensed Matter Physics Team

    Electric field-induced resistive switching (RS) effect has been widely explored as a novel nonvolatile memory over the past few years. Recently, the RS behavior with continuous transition has received considerable attention for its promising prospect in neuromorphic simulation. Here, the switching characteristics of a planar-structured TiOx single nanowire device were systematically investigated. It exhibited a strong electrical history-dependent rectifying behavior that was defined as a ''memdiode''. We further demonstrated that a ternary synaptic plasticity could be realized in such a TiOx nanowire device, characterized by the resistance and photocurrent responses. For a given state of the memdiode, a conjugated memristive characteristic and a distinct photocurrent can be simulaneously obtained, resulting in a synchronous implementation of various Hebbian plasticities with the same temporal order of spikes. These intriguing properties of TiOx memdiode provide a feasible way toward the designing of multifunctional electronic synapses as well as programmable artificial neural network This work has been partially supported by the National Basic Research of China (2013CB921700), the ``Strategic Priority Research Program (B)'' of the Chinese Academy of Sciences (XDB07030200) and the National Natural Science Foundation of China (11374339).

  13. Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke

    PubMed Central

    Stein, Efrat Shavit; Itsekson-Hayosh, Zeev; Aronovich, Anna; Reisner, Yair; Bushi, Doron; Pick, Chaim G.; Tanne, David; Chapman, Joab; Vlachos, Andreas; Maggio, Nicola

    2015-01-01

    Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke. PMID:25604482

  14. Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring

    PubMed Central

    Miner, Daniel; Triesch, Jochen

    2016-01-01

    Understanding the structure and dynamics of cortical connectivity is vital to understanding cortical function. Experimental data strongly suggest that local recurrent connectivity in the cortex is significantly non-random, exhibiting, for example, above-chance bidirectionality and an overrepresentation of certain triangular motifs. Additional evidence suggests a significant distance dependency to connectivity over a local scale of a few hundred microns, and particular patterns of synaptic turnover dynamics, including a heavy-tailed distribution of synaptic efficacies, a power law distribution of synaptic lifetimes, and a tendency for stronger synapses to be more stable over time. Understanding how many of these non-random features simultaneously arise would provide valuable insights into the development and function of the cortex. While previous work has modeled some of the individual features of local cortical wiring, there is no model that begins to comprehensively account for all of them. We present a spiking network model of a rodent Layer 5 cortical slice which, via the interactions of a few simple biologically motivated intrinsic, synaptic, and structural plasticity mechanisms, qualitatively reproduces these non-random effects when combined with simple topological constraints. Our model suggests that mechanisms of self-organization arising from a small number of plasticity rules provide a parsimonious explanation for numerous experimentally observed non-random features of recurrent cortical wiring. Interestingly, similar mechanisms have been shown to endow recurrent networks with powerful learning abilities, suggesting that these mechanism are central to understanding both structure and function of cortical synaptic wiring. PMID:26866369

  15. EDITORIAL: Synaptic electronics Synaptic electronics

    NASA Astrophysics Data System (ADS)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    integrated memristors Nanotechnology 24 384011 [7] Timm C and Di Ventra M 2013 Molecular neuron based on the Franck-Condon blockade Nanotechnology 24 384001 [8] Sillin H O, Aguilera R, Shieh H-H, Avizienis A V, Aono M, Stieg A Z and Gimzewski J K 2013 A theoretical and experimental study of neuromorphic atomic switch networks for reservoir computing Nanotechnology 24 384004 [9] Linn E, Menzel S, Ferch S and Waser R 2013 Compact modeling of CRS devices based on ECM cells for memory, logic and neuromorphic applications Nanotechnology 24 384008 [10] Konkoli Z and Wendin G 2013 A generic simulator for large networks of memristive elements Nanotechnology 24 384007 [11] Gacem K, Retrouvey J-M, Chabi D, Filoramo A, Zhao W, Klein J-O and Derycke V 2013 Neuromorphic function learning with carbon nanotube-based synapses Nanotechnology 24 384013 [12] Lim H, Kim I, Kim J-S, Hwang C S and Jeong D S 2013 Short-term memory of TiO2-based electrochemical capacitors: empirical analysis with adoption of a sliding threshold Nanotechnology 24 384005 [13] Park S, Noh J, Choo M-L, Sheri A M, Chang M, Kim Y-B, Kim C J, Jeon M, Lee B-G, Lee B H and Hwang H 2013 Nanoscale RRAM-based synaptic electronics: toward a neuromorphic computing device Nanotechnology 24 384009 [14] Yang R, Terabe K, Yao Y, Tsuruoka T, Hasegawa T, Gimzewski J K and Aono M 2013 Synaptic plasticity and memory functions achieved in WO3-x-based nanoionics device by using principle of atomic switch operation Nanotechnology 24 384002 [15] Ambrogio S, Balatti S, Nardi F, Facchinetti S and Ielmini D 2013 Spike-timing dependent plasticity in a transistor-selected resistive switching memory Nanotechnology 24 384012 [16] Indiveria G, Linares-Barranco B, Legenstein R, Deligeorgis G and Prodromakise T 2013 Integration of nanoscale memristor synapses in neuromorphic computing architectures Nanotechnology 24 384010 [17] Hino T, Hasegawa T, Tanaka H, Tsuruoka T, Terabe K, Ogawa T and Aono M 2013 Volatile and nonvolatile selective switching of

  16. Neutralization of Nogo-A Enhances Synaptic Plasticity in the Rodent Motor Cortex and Improves Motor Learning in Vivo

    PubMed Central

    Weinmann, Oliver; Kellner, Yves; Yu, Xinzhu; Vicente, Raul; Gullo, Miriam; Kasper, Hansjörg; Lussi, Karin; Ristic, Zorica; Luft, Andreas R.; Rioult-Pedotti, Mengia; Zuo, Yi; Zagrebelsky, Marta; Schwab, Martin E.

    2014-01-01

    The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex. PMID:24966370

  17. Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease.

    PubMed

    Zhang, Hua; Liu, Jie; Sun, Suya; Pchitskaya, Ekaterina; Popugaeva, Elena; Bezprozvanny, Ilya

    2015-01-01

    Alzheimer's disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand the basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by an abnormal firing pattern during the consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels, and increased afterhyperpolarization. As a result, "consolidation" pattern of neuronal activity converted to "depotentiation" pattern of neuronal activity in KI neurons. Consistent with this model, we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin), and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. This proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline.

  18. Cell biology of normal brain aging: synaptic plasticity-cell death.

    PubMed

    Dorszewska, Jolanta

    2013-04-01

    Senescence of the brain seems to be related to increased levels of free oxygen radical (FOR). FOR may damage macromolecular compounds such as: proteins, lipids, and DNA. In the aging brain, increased FOR levels damage DNA, mitochondrial DNA (mtDNA), and nuclear DNA (nDNA). In DNA they damage single and double strands, leading to mutations in mtDNA and nDNA. Damage to mtDNA seems to result in decay of mitochondria, decreased production of ATP, and in the activation of the apoptotic process. In the aging brain, apoptosis does not seem to be activated in wild-type p53-expressing cells because the elevated levels of the p53 protein are no longer accompanied by decreased levels of the Bcl-2 protein and increased levels of the Bax protein. It seems that, in the aging brain, changes in the metabolism of neurons may lead to their decreased numbers in the cerebral and cerebellar cortex, hippocampus, basal nucleus of Meynert, locus ceruleus, and substantia nigra, as well as to decreased numbers of synapses and disturbed stimulation of synaptic plasticity in the senescent brain. Simultaneously, a decrease in neurogenesis in the aging brain may lead to a decline in the maintenance of tissue integrity, function, and regenerative response. Environmental enrichment and physical activity may improve hippocampal neurogenesis and induce neuronal plasticity. The morphological lesions in the senescent brain are undoubtedly followed by a disturbed balance between various types of neurons in the CNS. Nevertheless, the high plasticity of the CNS in humans most probably does not allow for the development of abnormalities in higher functions. PMID:23740630

  19. Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats.

    PubMed

    Xiao, Yongmei; Fu, Hongjun; Han, Xiaojie; Hu, Xiaoxia; Gu, Huaiyu; Chen, Yilin; Wei, Qing; Hu, Qiansheng

    2014-01-01

    Lead (Pb) is found to impair cognitive function. Synaptic structural plasticity is considered to be the physiological basis of synaptic functional plasticity and has been recently found to play important roles in learning and memory. To study the effect of Pb on spatial learning and memory at different developmental stages, and its relationship with alterations of synaptic structural plasticity, postnatal rats were randomly divided into three groups: Control; Pre-weaning Pb (Parents were exposed to 2 mM PbCl2 3 weeks before mating until weaning of pups); Post-weaning Pb (Weaned pups were exposed to 2 mM PbCl2 for 9 weeks). The spatial learning and memory of rats was measured by Morris water maze (MWM) on PND 85-90. Rat pups in Pre-weaning Pb and Post-weaning Pb groups performed significantly worse than those in Control group (p<0.05). However, there was no significant difference in the performance of MWM between the two Pb-exposure groups. Before MWM (PND 84), the number of neurons and synapses significantly decreased in Pre-weaning Pb group, but not in Post-weaning Pb group. After MWM (PND 91), the number of synapses in Pre-weaning Pb group increased significantly, but it was still less than that of Control group (p<0.05); the number of synapses in Post-weaning Pb group was also less than that of Control group (p<0.05), although the number of synapses has no differences between Post-weaning Pb and Control groups before MWM. In both Pre-weaning Pb and Post-weaning Pb groups, synaptic structural parameters such as thickness of postsynaptic density (PSD), length of synaptic active zone and synaptic curvature increased significantly while width of synaptic cleft decreased significantly compared to Control group (p<0.05). Our data demonstrated that both early and late developmental Pb exposure impaired spatial learning and memory as well as synaptic structural plasticity in Wistar rats.

  20. Developmental effect of light deprivation on synaptic plasticity of rats’ hippocampus: implications for melatonin

    PubMed Central

    Talaei, Sayyed Alireza; Azami, Abolfazl; Salami, Mahmoud

    2016-01-01

    Objective(s): There are few reports have demonstrated the effect of a change-in-light experience on the structure and function of hippocampus. A change-in-light experience also affects the circadian pattern of melatonin secretion. This study aimed to investigate developmental effect of exogenous melatonin on synaptic plasticity of hippocampus of light deprived rats. Materials and Methods: The effects of intracerebroventricular (ICV) injection of 2μg/5μl melatonin was evaluated on the basic and tetanized field excitatory post-synaptic potentials (fEPSPs) recorded in the hippocampal CA3-CA1 pathway of normal light-reared (LR) and dark-reared (DR) rats at 2, 4, and 6 weeks of age. Using RT-PCR and western blotting, developmental changes in the expression of melatonin receptors, MT1 and MT2, in the hippocampus were also evaluated. Results: The amplitude of basic responses decreased across age in the LR rats. While light deprivation increased the amplitude of baseline fEPSPs, it decreased the degree of potentiation in post-tetanus responses. Melatonin injection also increased the amplitude of fEPSPs and suppressed the induction of long-term potentiation in both LR and DR rats. The expression of melatonin receptors increased in the hippocampus during brain development, and dark rearing reversed the expression patterns of both receptors. Conclusion: Although melatonin changed basic and tetanized responses of CA1 neurons across age during critical period of brain development, the pattern of its effects did not match the expression pattern of melatonin receptors in the hippocampus. Thus, the effects of melatonin on hippocampal neuronal responses may be exerted through other ways, like intercellular molecules and nuclear hormone receptors. PMID:27746873

  1. Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation

    PubMed Central

    López, Alberto J.; Kramár, Enikö; Matheos, Dina P.; White, André O.; Kwapis, Janine; Vogel-Ciernia, Annie; Sakata, Keith; Espinoza, Monica

    2016-01-01

    drug (DREADDs) as a means of bidirectionally modulating the hippocampus in not only a hippocampus-dependent task but also in hippocampal synaptic plasticity. This is the first study to evaluate the effects of DREADD-mediated inhibition and excitation in hippocampal long-term potentiation. More specifically, this study evaluates the effect of promoter-specific expression of DREADD viruses in a heterogenic cell population, which revealed surprising effects of different promoters. With chemogenetics becoming a more ubiquitous tool throughout studies investigating circuit-specific function, these data are of broad interest to the neuroscientific community because we have shown that promoter-specific effects can drastically alter synaptic function within a specific region, without parallel changes at the level of behavior. PMID:27013687

  2. Effects of lipopolysaccharide on 56Fe-particle radiation-induced impairment of synaptic plasticity in the mouse hippocampus.

    PubMed

    Vlkolinský, Roman; Krucker, Thomas; Smith, Anna L; Lamp, Tyra C; Nelson, Gregory A; Obenaus, Andre

    2007-10-01

    Space radiation, including high-mass, high-Z, high-energy particles (HZE; e.g. (56)Fe), represents a significant health risk for astronauts, and the central nervous system (CNS) may be a vulnerable target. HZE-particle radiation may directly affect neuronal function, or during immunological challenge, it may alter immune system-to-CNS communication. To test these hypotheses, we exposed mice to accelerated iron particles ((56)Fe; 600 MeV/nucleon; 1, 2, 4 Gy; brain only) and 1 month later prepared hippocampal slices to measure the effects of radiation on neurotransmission and synaptic plasticity in CA1 neurons. In a model of immune system-to-CNS communication, these electrophysiological parameters were measured in irradiated mice additionally challenged with the peripheral immunological stressor lipopolysaccharide (LPS) injected intraperitoneally 4 h before the slice preparation. Exposure to (56)Fe particles alone increased dendritic excitability and inhibited plasticity. In control mice (0 Gy), LPS treatment also inhibited synaptic plasticity. Paradoxically, in mice exposed to 2 Gy, the LPS treatment restored synaptic plasticity to levels similar to those found in controls (0 Gy, no LPS). Our results indicate that HZE-particle radiation alters normal electrophysiological properties of the CNS and the hippocampal response to LPS. PMID:17903042

  3. Gravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory.

    PubMed

    Havekes, Robbert; Canton, David A; Park, Alan J; Huang, Ted; Nie, Ting; Day, Jonathan P; Guercio, Leonardo A; Grimes, Quinn; Luczak, Vincent; Gelman, Irwin H; Baillie, George S; Scott, John D; Abel, Ted

    2012-12-12

    A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage.

  4. Acute stress and hippocampal output: exploring dorsal CA1 and subicular synaptic plasticity simultaneously in anesthetized rats

    PubMed Central

    MacDougall, Matthew J; Howland, John G

    2013-01-01

    The Cornu Ammonis-1 (CA1) subfield and subiculum (SUB) serve as major output structures of the hippocampal formation. Exploring forms of synaptic plasticity simultaneously within these two output regions may improve understanding of the dynamics of hippocampal circuitry and information transfer between hippocampal and cortical brain regions. Using a novel dual-channel electrophysiological preparation in urethane-anesthetized adult male Sprague-Dawley rats in vivo, we examined the effects of acute restraint stress (30 min) on short- and long-term forms of synaptic plasticity in both CA1 and SUB by stimulating the CA3 region. Paired-pulse facilitation was disrupted in SUB but not CA1 in the dual-channel experiments following exposure to acute stress. Disruptions in CA1 PPF were evident in subsequent single-channel experiments with a more anterior recording site. Acute stress disrupted long-term potentiation induced by high-frequency stimulation (10 bursts of 20 pulses at 200 Hz) in both CA1 and SUB. Low-frequency stimulation (900 pulses at 1 Hz) did not alter CA1 plasticity while a late-developing potentiation was evident in SUB that was disrupted following exposure to acute stress. These findings highlight differences in the sensitivity to acute stress for distinct forms of synaptic plasticity within synapses in hippocampal output regions. The findings are discussed in relation to normal and aberrant forms of hippocampal-cortical information processing. PMID:24303119

  5. Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice

    PubMed Central

    Kelly, Emily A.; Russo, Amanda S.; Jackson, Cory D.; Lamantia, Cassandra E.; Majewska, Ania K.

    2015-01-01

    The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex. PMID:26441540

  6. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.

    PubMed

    Royer, S; Paré, D

    2002-01-01

    Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. Because they control impulse traffic from the basolateral amygdala to the central nucleus, GABAergic neurons of the intercalated cell masses are ideally located to implement this second learning. Consistent with this hypothesis, the present study shows that low- and high-frequency stimulation of basolateral afferents respectively induce long-term depression (LTD) and potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP and LTD is prevented by application of an NMDA antagonist. To determine how these activity-dependent changes are expressed, we tested whether LTD and LTP induction are associated with modifications in paired-pulse facilitation, an index of transmitter release probability. Only LTP induction was associated with a change in paired-pulse facilitation. Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.

  7. The effects of L-arginine on spatial memory and synaptic plasticity impairments induced by lipopolysaccharide

    PubMed Central

    Anaeigoudari, Akbar; Shafei, Mohammad Naser; Soukhtanloo, Mohammad; Sadeghnia, Hamid Reza; Reisi, Parham; Nosratabadi, Reza; Behradnia, Sepehr; Hosseini, Mahmoud

    2015-01-01

    Background: An important role of nitric oxide (NO) in neuroinflammation has been suggested. It is also suggested that NO has a critical role in learning and memory. Neuro-inflammation induced by lipopolysaccharide (LPS) has been reported that deteriorates learning and memory. The effect of L-arginine (LA) as a precursor of NO on LPS-induced spatial learning and memory and neuronal plasticity impairment was evaluated. Materials and Methods: The animals were grouped into: (1) Control, (2) LPS, (3) LA-LPS, and (4) LA. The rats received intraperitoneally LPS (1 mg/kg) 2 h before experiments and LA (200 mg/kg) 30 min before LPS. The animals were examined in Morris water maze (MWM). Long-term potentiation (LTP) from CA1 area of the hippocampus was also assessed by 100 Hz stimulation in the ipsilateral Schaffer collateral pathway. Results: In MWM, time latency and traveled path were higher in LPS group than the control group (P < 0.001) whereas in LA-LPS group they were shorter than LPS group (P < 0.001). The amplitude and slope of field excitatory postsynaptic potential (fEPSP) decreased in LPS group compared to control group (P < 0.05 and P < 0.01) whereas, there was not any significant difference in these parameters between LPS and LA-LPS groups. Conclusion: Administration of LPS impaired spatial memory and synaptic plasticity. Although LA ameliorated deleterious effects of LPS on learning of spatial tasks, it could not restore LPS-induced LTP impairment. PMID:26601090

  8. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine

    PubMed Central

    Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan

    2009-01-01

    DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been

  9. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine.

    PubMed

    Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan; Standaert, David G; Pisani, Antonio

    2009-09-01

    DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been

  10. Synapse-specific stabilization of plasticity processes: the synaptic tagging and capture hypothesis revisited 10 years later.

    PubMed

    Barco, Angel; Lopez de Armentia, Mikel; Alarcon, Juan M

    2008-01-01

    A decade ago, the synaptic tagging hypothesis was proposed to explain how newly synthesized plasticity products can be specifically targeted to active synapses. A growing number of studies have validated the seminal findings that gave rise to this model, as well as contributed to unveil and expand the range of mechanisms underlying late-associativity and neuronal computation. Here, we will review what it was learnt during this past decade regarding the cellular and molecular mechanisms underlying synaptic tagging and synaptic capture. The accumulated experimental evidence has widened the theoretical framework set by the synaptic tagging and capture (STC) model and introduced concepts that were originally considered part of alternative models for explaining synapse-specific long-term potentiation (LTP). As a result, we believe that the STC model, now improved and expanded with these new ideas and concepts, still represents the most compelling hypothesis to explain late-associativity in synapse-specific plasticity processes. We will also discuss the impact of this model in our view of the integrative capability of neurons and associative learning. PMID:18281094

  11. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity.

    PubMed

    Wang, Hui; Peng, Rui-Yun

    2016-01-01

    With key roles in essential brain functions ranging from the long-term potentiation (LTP) to synaptic plasticity, the N-methyl-D-aspartic acid receptor (NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system. The role of NMDA R was first identified in synaptic plasticity and has been extensively studied. Some molecules, such as Ca(2+), postsynaptic density 95 (PSD-95), calcium/calmodulin-dependent protein kinase II (CaMK II), protein kinase A (PKA), mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), are of special importance in learning and memory. This review mainly focused on the new research of key molecules connected with learning and memory, which played important roles in the NMDAR signaling pathway. PMID:27583167

  12. Short-term intercultural psychotherapy: ethnographic inquiry.

    PubMed

    Seeley, Karen M

    2004-01-01

    This article examines the challenges specific to short-term intercultural treatments and recently developed approaches to intercultural treatments based on notions of cultural knowledge and cultural competence. The article introduces alternative approaches to short-term intercultural treatments based on ethnographic inquiry adapted for clinical practice. Such approaches allow clinicians conducting short-term intercultural treatments to foreground clients' indigenous conceptions of selfhood, mind, relationship, and emotional disturbance, and thus to more fully grasp their internal, interpersonal, and external worlds. This article demonstrates the uses of clinically adapted ethnographic inquiry in three short-term intercultural cases. PMID:14964524

  13. Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity.

    PubMed

    Kluge, Christian; Stoppel, Christian; Szinyei, Csaba; Stork, Oliver; Pape, Hans-Christian

    2008-04-01

    Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.

  14. Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity

    PubMed Central

    Thibault, Karine; Rivière, Sébastien; Lenkei, Zsolt

    2016-01-01

    Chronic pain is a long-lasting debilitating condition that is particularly difficult to treat due to the lack of identified underlying mechanisms. Although several key contributing processes have been described at the level of the spinal cord, very few studies have investigated the supraspinal mechanisms underlying chronic pain. Using a combination of approaches (cortical intrinsic imaging, immunohistochemical and behavioural analysis), our study aimed to decipher the nature of functional and structural changes in a mouse model of orofacial neuropathic pain, focusing on cortical areas involved in various pain components. Our results show that chronic neuropathic orofacial pain is associated with decreased haemodynamic responsiveness to whisker stimulation in the barrel field cortex. This reduced functional activation is likely due to the increased basal neuronal activity (measured indirectly using cFos and phospho-ERK immunoreactivity) observed in several cortical areas, including the contralateral barrel field, motor and cingulate cortices. In the same animals, immunohistochemical analysis of markers for active pre- or postsynaptic elements (Piccolo and phospho-Cofilin, respectively) revealed an increased immunofluorescence in deep cortical layers of the contralateral barrel field, motor and cingulate cortices. These results suggest that long-lasting orofacial neuropathic pain is associated with exacerbated neuronal activity and synaptic plasticity at the cortical level. PMID:27548330

  15. Structure-function-behavior relationship in estrogen-induced synaptic plasticity.

    PubMed

    Vierk, R; Bayer, J; Freitag, S; Muhia, M; Kutsche, K; Wolbers, T; Kneussel, M; Sommer, T; Rune, G M

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". In estrogen-induced synaptic plasticity, a correlation of structure, function and behavior in the hippocampus has been widely established. 17ß-estradiol has been shown to increase dendritic spine density on hippocampal neurons and is accompanied by enhanced long-term potentiation and improved performance of animals in hippocampus-dependent memory tests. After inhibition of aromatase, the final enzyme of estradiol synthesis, with letrozole we consistently found a strong and significant impairment of long-term potentiation (LTP) in female mice as early as after six hours of treatment. LTP impairment was followed by loss of hippocampal spine synapses in the hippocampal CA1 area. Interestingly, these effects were not found in male animals. In the Morris water maze test, chronic administration of letrozole did not alter spatial learning and memory in either female or male mice. In humans, analogous effects of estradiol on hippocampal morphology and physiology were observed using neuroimaging techniques. However, similar to our findings in mice, an effect of estradiol on memory performance has not been consistently observed.

  16. Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36

    NASA Astrophysics Data System (ADS)

    Palacios-Prado, Nicolás; Chapuis, Sandrine; Panjkovich, Alejandro; Fregeac, Julien; Nagy, James I.; Bukauskas, Feliksas F.

    2014-08-01

    Neuronal gap junction (GJ) channels composed of connexin36 (Cx36) play an important role in neuronal synchronization and network dynamics. Here we show that Cx36-containing electrical synapses between inhibitory neurons of the thalamic reticular nucleus are bidirectionally modulated by changes in intracellular free magnesium concentration ([Mg2+]i). Chimeragenesis demonstrates that the first extracellular loop of Cx36 contains a Mg2+-sensitive domain, and site-directed mutagenesis shows that the pore-lining residue D47 is critical in determining high Mg2+-sensitivity. Single-channel analysis of Mg2+-sensitive chimeras and mutants reveals that [Mg2+]i controls the strength of electrical coupling mostly via gating mechanisms. In addition, asymmetric transjunctional [Mg2+]i induces strong instantaneous rectification, providing a novel mechanism for electrical rectification in homotypic Cx36 GJs. We suggest that Mg2+-dependent synaptic plasticity of Cx36-containing electrical synapses could underlie neuronal circuit reconfiguration via changes in brain energy metabolism that affects neuronal levels of intracellular ATP and [Mg2+]i.

  17. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice

    PubMed Central

    Dai, Hai-long; Hu, Wei-yuan; Jiang, Li-hong; Li, Le; Gaung, Xue-feng; Xiao, Zhi-cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  18. Role of Nicotinic and Muscarinic Receptors on Synaptic Plasticity and Neurological Diseases.

    PubMed

    Fuenzalida, Marco; Pérez, Miguel Ángel; Arias, Hugo R

    2016-01-01

    The cholinergic activity in the brain is fundamental for cognitive functions. The modulatory activity of the neurotransmitter acetylcholine (ACh) is mediated by activating a variety of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Accumulating evidence indicates that both nAChR and mAChRs can modulate the release of several other neurotransmitters, modify the threshold of long-term plasticity, finally improving learning and memory processes. Importantly, the expression, distribution, and/or function of these systems are altered in several neurological diseases. The aim of this review is to discuss our current knowledge on cholinergic receptors and their regulating synaptic functions and neuronal network activities as well as their use as targets for the development of new and clinically useful cholinergic ligands. These new therapies involve the development of novel and more selective cholinergic agonists and allosteric modulators as well as selective cholinesterase inhibitors, which may improve cognitive and behavioral symptoms, and also provide neuroprotection in several brain diseases. The review will focus on two nAChR receptor subtypes found in the mammalian brain and the most commonly targeted in drug discovery programs for neuropsychiatric disorder, the ligands of α4β2 nAChR and α7 nAChRs. PMID:26818867

  19. Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice.

    PubMed

    Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori; Matozaki, Takashi; Ohnishi, Hiroshi

    2015-05-01

    Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K(+)-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

  20. Dopamine-dependent synaptic plasticity in an amygdala inhibitory circuit controls fear memory expression.

    PubMed

    Lee, Joo Han; Kim, Joung-Hun

    2016-01-01

    Of the numerous events that occur in daily life, we readily remember salient information, but do not retain most less-salient events for a prolonged period. Although some of the episodes contain putatively emotional aspects, the information with lower saliency is rarely stored in neural circuits via an unknown mechanism. We provided substantial evidence indicating that synaptic plasticity in the dorsal ITC of amygdala allows for selective storage of salient emotional experiences, while it deters less-salient experience from entering long-term memory. After activation of D4R or weak fear conditioning, STDP stimulation induces LTD in the LA-ITC synapses. This form of LTD is dependent upon presynaptic D4R, and is likely to result from enhancement of GABA release. Both optogenetic abrogation of LTD and ablation of D4R at the dorsal ITC in vivo lead to heightened and over-generalized fear responses. Finally, we demonstrated that LTD was impaired at the dorsal ITC of PTSD model mice, which suggests that maladaptation of GABAergic signaling and the resultant LTD impairment contribute to the endophenotypes of PTSD. PMID:26674344

  1. Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome.

    PubMed

    Servais, Laurent; Hourez, Raphaël; Bearzatto, Bertrand; Gall, David; Schiffmann, Serge N; Cheron, Guy

    2007-06-01

    In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the gamma-isoform of protein kinase C. Long-term depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of long-term synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder.

  2. Modulation of network activity and induction of homeostatic synaptic plasticity by enzymatic removal of heparan sulfates

    PubMed Central

    Korotchenko, Svetlana; Cingolani, Lorenzo A.; Kuznetsova, Tatiana; Bologna, Luca Leonardo; Chiappalone, Michela; Dityatev, Alexander

    2014-01-01

    Heparan sulfates (HSs) are complex and highly active molecules that are required for synaptogenesis and long-term potentiation. A deficit in HSs leads to autistic phenotype in mice. Here, we investigated the long-term effect of heparinase I, which digests highly sulfated HSs, on the spontaneous bioelectrical activity of neuronal networks in developing primary hippocampal cultures. We found that chronic heparinase treatment led to a significant reduction of the mean firing rate of neurons, particularly during the period of maximal neuronal activity. Furthermore, firing pattern in heparinase-treated cultures often appeared as epileptiform bursts, with long periods of inactivity between them. These changes in network activity were accompanied by an increase in the frequency and amplitude of miniature postsynaptic excitatory currents, which could be described by a linear up-scaling of current amplitudes. Biochemically, we observed an upregulation in the expression of the glutamate receptor subunit GluA1, but not GluA2, and a strong increase in autophosphorylation of α and β Ca2+/calmodulin-dependent protein kinase II (CaMKII), without changes in the levels of kinase expression. These data suggest that a deficit in HSs triggers homeostatic synaptic plasticity and drastically affects functional maturation of neural network. PMID:25225107

  3. Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

    PubMed Central

    Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori

    2015-01-01

    Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation. PMID:25713104

  4. Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity

    PubMed Central

    Cichon, Joseph; Gan, Wen-Biao

    2015-01-01

    The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca2+ spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca2+ spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca2+ spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca2+ spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences. PMID:25822789

  5. Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity.

    PubMed

    Thibault, Karine; Rivière, Sébastien; Lenkei, Zsolt; Férézou, Isabelle; Pezet, Sophie

    2016-01-01

    Chronic pain is a long-lasting debilitating condition that is particularly difficult to treat due to the lack of identified underlying mechanisms. Although several key contributing processes have been described at the level of the spinal cord, very few studies have investigated the supraspinal mechanisms underlying chronic pain. Using a combination of approaches (cortical intrinsic imaging, immunohistochemical and behavioural analysis), our study aimed to decipher the nature of functional and structural changes in a mouse model of orofacial neuropathic pain, focusing on cortical areas involved in various pain components. Our results show that chronic neuropathic orofacial pain is associated with decreased haemodynamic responsiveness to whisker stimulation in the barrel field cortex. This reduced functional activation is likely due to the increased basal neuronal activity (measured indirectly using cFos and phospho-ERK immunoreactivity) observed in several cortical areas, including the contralateral barrel field, motor and cingulate cortices. In the same animals, immunohistochemical analysis of markers for active pre- or postsynaptic elements (Piccolo and phospho-Cofilin, respectively) revealed an increased immunofluorescence in deep cortical layers of the contralateral barrel field, motor and cingulate cortices. These results suggest that long-lasting orofacial neuropathic pain is associated with exacerbated neuronal activity and synaptic plasticity at the cortical level. PMID:27548330

  6. Effects of exercise intensity on spatial memory performance and hippocampal synaptic plasticity in transient brain ischemic rats.

    PubMed

    Shih, Pei-Cheng; Yang, Yea-Ru; Wang, Ray-Yau

    2013-01-01

    Memory impairment is commonly noted in stroke survivors, and can lead to delay of functional recovery. Exercise has been proved to improve memory in adult healthy subjects. Such beneficial effects are often suggested to relate to hippocampal synaptic plasticity, which is important for memory processing. Previous evidence showed that in normal rats, low intensity exercise can improve synaptic plasticity better than high intensity exercise. However, the effects of exercise intensities on hippocampal synaptic plasticity and spatial memory after brain ischemia remain unclear. In this study, we investigated such effects in brain ischemic rats. The middle cerebral artery occlusion (MCAO) procedure was used to induce brain ischemia. After the MCAO procedure, rats were randomly assigned to sedentary (Sed), low-intensity exercise (Low-Ex), or high-intensity exercise (High-Ex) group. Treadmill training began from the second day post MCAO procedure, 30 min/day for 14 consecutive days for the exercise groups. The Low-Ex group was trained at the speed of 8 m/min, while the High-Ex group at the speed of 20 m/min. The spatial memory, hippocampal brain-derived neurotrophic factor (BDNF), synapsin-I, postsynaptic density protein 95 (PSD-95), and dendritic structures were examined to document the effects. Serum corticosterone level was also quantified as stress marker. Our results showed the Low-Ex group, but not the High-Ex group, demonstrated better spatial memory performance than the Sed group. Dendritic complexity and the levels of BDNF and PSD-95 increased significantly only in the Low-Ex group as compared with the Sed group in bilateral hippocampus. Notably, increased level of corticosterone was found in the High-Ex group, implicating higher stress response. In conclusion, after brain ischemia, low intensity exercise may result in better synaptic plasticity and spatial memory performance than high intensity exercise; therefore, the intensity is suggested to be considered

  7. Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity.

    PubMed

    Vaynman, S; Ying, Z; Wu, A; Gomez-Pinilla, F

    2006-01-01

    Synaptic plasticity and behaviors are likely dependent on the capacity of neurons to meet the energy demands imposed by neuronal activity. We used physical activity, a paradigm intrinsically associated with energy consumption/expenditure and cognitive enhancement, to study how energy metabolism interacts with the substrates for neuroplasticity. We found that in an area critical for learning and memory, the hippocampus, exercise modified aspects of energy metabolism by decreasing oxidative stress and increasing the levels of cytochrome c oxidase-II, a specific component of mitochondrial machinery. We infused 1,25-dihydroxyvitamin D3, a modulator of energy metabolism, directly into the hippocampus during 3 days of voluntary wheel running and measured its effects on brain-derived neurotrophic factor-mediated synaptic plasticity. Brain-derived neurotrophic factor is a central player for the effects of exercise on synaptic and cognitive plasticity. We found that 25-dihydroxyvitamin D3 decreased exercise-induced brain-derived neurotrophic factor but had no significant effect on neurotrophin-3 levels, thereby suggesting a level of specificity for brain-derived neurotrophic factor in the hippocampus. 25-Dihydroxyvitamin D3 injection also abolished the effects of exercise on the consummate end-products of brain-derived neurotrophic factor action, i.e. cyclic AMP response element-binding protein and synapsin I, and modulated phosphorylated calmodulin protein kinase II, a signal transduction cascade downstream to brain-derived neurotrophic factor action that is important for learning and memory. We also found that exercise significantly increased the expression of the mitochondrial uncoupling protein 2, an energy-balancing factor concerned with ATP production and free radical management. Our results reveal a fundamental mechanism by which key elements of energy metabolism may modulate the substrates of hippocampal synaptic plasticity.

  8. Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression

    PubMed Central

    Gómez-Galán, Marta; Femenía, Teresa; Åberg, Elin; Graae, Lisette; Van Eeckhaut, Ann; Smolders, Ilse; Brené, Stefan; Lindskog, Maria

    2016-01-01

    Stress, such as social isolation, is a well-known risk factor for depression, most probably in combination with predisposing genetic factors. Physical exercise on the other hand, is depicted as a wonder-treatment that makes you healthier, happier and live longer. However, the published results on the effects of exercise are ambiguous, especially when it comes to neuropsychiatric disorders. Here we combine a paradigm of social isolation with a genetic rat model of depression, the Flinders Sensitive Line (FSL), already known to have glutamatergic synaptic alterations. Compared to group-housed FSL rats, we found that social isolation further affects synaptic plasticity and increases basal synaptic transmission in hippocampal CA1 pyramidal neurons. These functional synaptic alterations co-exist with changes in hippocampal protein expression levels: social isolation in FSL rats reduce expression of the glial glutamate transporter GLT-1, and increase expression of the GluA2 AMPA-receptor subunit. We further show that physical exercise in form of voluntary running prevents the stress-induced synaptic effects but do not restore the endogenous mechanisms of depression already present in the FSL rat. PMID:27764188

  9. Synaptic and circuit mechanisms promoting broadband transmission of olfactory stimulus dynamics

    PubMed Central

    Nagel, Katherine I.; Hong, Elizabeth J.; Wilson, Rachel I.

    2014-01-01

    Sensory stimuli fluctuate on many timescales. However, short-term plasticity causes synapses to act as temporal filters, limiting the range of frequencies they can transmit. How synapses in vivo might transmit a range of frequencies in spite of short-term plasticity is poorly understood. The first synapse in the Drosophila olfactory system exhibits short-term depression, and yet can transmit broadband signals. Here we describe two mechanisms that broaden the frequency characteristics of this synapse. First, two distinct excitatory postsynaptic currents transmit signals on different timescales. Second, presynaptic inhibition dynamically updates synaptic properties to promote accurate transmission of signals across a wide range of frequencies. Inhibition is transient but grows slowly, and simulations show that these two features of inhibition promote broadband synaptic transmission. Dynamic inhibition is often thought to restrict the temporal patterns that a neuron responds to, but our results illustrate a different idea: inhibition can expand the bandwidth of neural coding. PMID:25485755

  10. The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

    PubMed Central

    Arzt, Michael E.; Weinmann, Oliver; Obermair, Franz J.; Pernet, Vincent; Zagrebelsky, Marta; Delekate, Andrea; Iobbi, Cristina; Zemmar, Ajmal; Ristic, Zorica; Gullo, Miriam; Spies, Peter; Dodd, Dana; Gygax, Daniel; Korte, Martin; Schwab, Martin E.

    2014-01-01

    Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A−/− mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity. PMID:24453941

  11. A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.

    PubMed

    Kong, Dong; Dagon, Yossi; Campbell, John N; Guo, Yikun; Yang, Zongfang; Yi, Xinchi; Aryal, Pratik; Wellenstein, Kerry; Kahn, Barbara B; Sabatini, Bernardo L; Lowell, Bradford B

    2016-07-01

    AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity. PMID:27321921

  12. Quercetin relieves chronic lead exposure-induced impairment of synaptic plasticity in rat dentate gyrus in vivo.

    PubMed

    Hu, Pu; Wang, Ming; Chen, Wei-Heng; Liu, Ji; Chen, Liang; Yin, Shu-Ting; Yong, Wu; Chen, Ju-Tao; Wang, Hui-Li; Ruan, Di-Yun

    2008-07-01

    Increasing evidence suggests that lead (Pb) produces impairments partly through oxidative stress. Though many researchers have investigated protective effect of some antioxidant nutrients against Pb toxicity, little information is available about the effect of antioxidants on Pb-induced impairment of synaptic plasticity. Quercetin, a strong antioxidant and radical scavenger, is the representative natural flavonoid molecule abundant in fruits and vegetables. Previous studies have found that quercetin was neuroprotective in many cases. This study was designed to evaluate the effect of quercetin on chronic Pb exposure-induced impairment of synaptic plasticity in adult rat dentate gyrus (DG) area in vivo. The input/output (I/O) functions, paired-pulse reactions (PPR), excitatory postsynaptic potential (EPSP), and population spike (PS) amplitude were measured in the DG area of different groups of rats in response to stimulation applied to the lateral perforant path. The results showed that the depressed I/O, PPR, and long-term potentiation (LTP) of Pb-exposed group were significantly increased by quercetin treatment. In addition, hippocampal Pb concentration was partially reduced after quercetin treatment. These findings suggest that quercetin treatment could relieve chronic Pb exposure-induced impairment of synaptic plasticity and might be a potential therapeutic intervention to cure cognitive deficits induced by Pb.

  13. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons.

    PubMed

    Beckley, Jacob T; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A; Ron, Dorit

    2016-01-20

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. Significance statement: Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  14. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons.

    PubMed

    Beckley, Jacob T; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A; Ron, Dorit

    2016-01-20

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. Significance statement: Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  15. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons

    PubMed Central

    Beckley, Jacob T.; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A.

    2016-01-01

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. SIGNIFICANCE STATEMENT Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  16. MicroRNA Regulation of the Synaptic Plasticity-Related Gene Arc

    PubMed Central

    Siripornmongcolchai, Taweeporn; Bittins, Margarethe; Berentsen, Birgitte; Ofte, May Lillian; Weigel, Arwed; Skaftnesmo, Kai Ove; Bramham, Clive R.

    2012-01-01

    Expression of activity-regulated cytoskeleton associated protein (Arc) is crucial for diverse types of experience-dependent synaptic plasticity and long-term memory in mammals. However, the mechanisms governing Arc-specific translation are little understood. Here, we asked whether Arc translation is regulated by microRNAs. Bioinformatic analysis predicted numerous candidate miRNA binding sites within the Arc 3′-untranslated region (UTR). Transfection of the corresponding microRNAs in human embryonic kidney cells inhibited expression of an Arc 3′UTR luciferase reporter from between 10 to 70% across 16 microRNAs tested. Point mutation and deletion of the microRNA-binding seed-region for miR-34a, miR-326, and miR-19a partially or fully rescued reporter expression. In addition, expression of specific microRNA pairs synergistically modulated Arc reporter expression. In primary rat hippocampal neuronal cultures, ectopic expression of miR-34a, miR-193a, or miR-326, downregulated endogenous Arc protein expression in response to BDNF treatment. Conversely, treatment of neurons with cell-penetrating, peptide nucleic acid (PNA) inhibitors of miR-326 enhanced Arc mRNA expression. BDNF dramatically upregulated neuronal expression of Arc mRNA and miR-132, a known BDNF-induced miRNA, without affecting expression of Arc-targeting miRNAs. Developmentally, miR-132 was upregulated at day 10 in vitro whereas Arc-targeting miRNAs were downregulated. In the adult brain, LTP induction in the dentate gyrus triggered massive upregulation of Arc and upregulation of miR-132 without affecting levels of mature Arc-targeting miRNAs. Turning to examine miRNA localization, qPCR analysis of dentate gyrus synaptoneurosome and total lysates fractions demonstrated synaptic enrichment relative to small nucleolar RNA. In conclusion, we find that Arc is regulated by multiple miRNAs and modulated by specific miRNA pairs in vitro. Furthermore, we show that, in contrast to miR-132, steady state levels

  17. Short-Term Intercultural Psychotherapy: Ethnographic Inquiry

    ERIC Educational Resources Information Center

    Seeley, Karen M.

    2004-01-01

    This article examines the challenges specific to short-term intercultural treatments and recently developed approaches to intercultural treatments based on notions of cultural knowledge and cultural competence. The article introduces alternative approaches to short-term intercultural treatments based on ethnographic inquiry adapted for clinical…

  18. Effects of Early Life Stress on Synaptic Plasticity in the Developing Hippocampus of Male and Female Rats

    PubMed Central

    Krugers, Harm J.; Hoogenraad, Casper C.; Joëls, Marian; Sarabdjitsingh, R. Angela

    2016-01-01

    Introduction Early life stress (ELS) increases the risk for developing psychopathology in adulthood. When these effects occur is largely unknown. We here studied at which time during development ELS affects hippocampal synaptic plasticity, from early life to adulthood, in a rodent ELS model. Moreover, we investigated whether the sensitivity of synaptic plasticity to the stress-hormone corticosterone is altered by exposure to ELS. Materials & Methods Male and female Wistar rats were exposed to maternal deprivation (MD) for 24h on postnatal day (P)3 or left undisturbed with their mother (control). On P8-9, 22–24 and P85-95, plasma corticosterone (CORT) levels, body weight, and thymus and adrenal weights were determined to validate the neuroendocrine effects of MD. Field potentials in the CA1 hippocampus were recorded in vitro before and after high frequency stimulation. Brain slices were incubated for 20 min with 100nM CORT or vehicle 1-4h prior to high frequency stimulation, to mimic high-stress conditions in vitro. Results & Discussion Body weight was decreased by MD only at P4 (p = 0.02). There were minimal effects on P8-9, 22–24 or 85–95 thymus and adrenal weight and basal CORT levels. Glutamate transmission underwent strong developmental changes: half-maximal signal size strongly increased (p<0.0001) while the required half-maximal stimulation intensity concomitantly decreased with age (p = 0.04). Synaptic plasticity developed from long-term depression at P8-9 to increasing levels of long-term potentiation at later ages (p = 0.0001). MD caused a significant increase in long-term potentiation of P22-24 males (p = 0.03) and P85-95 females (p = 0.04). Bayesian modeling strongly supported the age-dependent development, with some evidence for accelerated maturation after MD in males (Bayes factor 1.23). CORT suppressed LTP in adult males; synaptic plasticity at other ages and in females remained unaffected. Thus, MD affects the development of synaptic

  19. Impaired ILK Function Is Associated with Deficits in Hippocampal Based Memory and Synaptic Plasticity in a FASD Rat Model

    PubMed Central

    Bhattacharya, D.; Dunaway, E. P.; Bhattacharya, S.; Bloemer, J.; Buabeid, M.; Escobar, M.

    2015-01-01

    Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term that encompasses a wide range of anatomical and behavioral problems in children who are exposed to alcohol during the prenatal period. There is no effective treatment for FASD, because of lack of complete characterization of the cellular and molecular mechanisms underlying this condition. Alcohol has been previously characterized to affect integrins and growth factor signaling receptors. Integrin Linked Kinase (ILK) is an effector of integrin and growth-factor signaling which regulates various signaling processes. In FASD, a downstream effector of ILK, Glycogen Synthase Kinase 3β (GSK3β) remains highly active (reduced Ser9 phosphorylation). GSK3β has been known to modulate glutamate receptor trafficking and channel properties. Therefore, we hypothesize that the cognitive deficits accompanying FASD are associated with impairments in the ILK signaling pathway. Pregnant Sprague Dawley rats consumed a “moderate” amount of alcohol throughout gestation, or a calorie-equivalent sucrose solution. Contextual fear conditioning was used to evaluate memory performance in 32–33-day-old pups. Synaptic plasticity was assessed in the Schaffer Collateral pathway, and hippocampal protein lysates were used to evaluate ILK signaling. Alcohol exposed pups showed impaired contextual fear conditioning, as compared to control pups. This reduced memory performance was consistent with decrease in LTP as compared to controls. Hippocampal ILK activity and GSK3β Ser21/9 phosphorylation were significantly lower in alcohol-exposed pups than controls. Increased synaptic expression of GluR2 AMPA receptors was observed with immunoprecipitation of post-synaptic density protein 95 (PSD95). Furthermore, immunoprecipitation of ILK revealed a decreased interaction with GluR2. The ILK pathway appears to play a significant role in memory and synaptic plasticity impairments in FASD rats. These impairments appear to be mediated by reduced

  20. Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors.

    PubMed

    Qi, Yong; Yang, Yunlei

    2015-09-23

    It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa.

  1. A novel function for serotonin-mediated short-term facilitation in Aplysia: Conversion of a transient, cell-wide homosynaptic Hebbian plasticity into a persistent, protein synthesis-independent synapse-specific enhancement

    PubMed Central

    Bailey, Craig H.; Giustetto, Maurizio; Zhu, Hiuxiang; Chen, Mary; Kandel, Eric R.

    2000-01-01

    Studies of sensitization and classical conditioning of the gill-withdrawal reflex in Aplysia have shown that the synaptic connections between identified glutamatergic sensory neurons and motor neurons can be enhanced in one of two ways: by a heterosynaptic (modulatory input-dependent