TrkB as a Potential Synaptic and Behavioral Tag

Gene, Cognition and Psychosis Program, NIMH, National Institutes of Health, Bethesda, Maryland 20892-3714, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2011; 31(33):11762-71. DOI: 10.1523/JNEUROSCI.2707-11.2011
Source: PubMed


Late-phase long-term potentiation (L-LTP), a cellular model for long-term memory (LTM), requires de novo protein synthesis. An attractive hypothesis for synapse specificity of long-term memory is "synaptic tagging": synaptic activity generates a tag, which "captures" the PRPs (plasticity-related proteins) derived outside of synapses. Here we provide evidence that TrkB, the receptor of BDNF (brain-derived neurotrophic factor), may serve as a "synaptic tag." TrkB is transiently activated by weak theta-burst stimulation (TBS) that induces only early-phase LTP (E-LTP). This TrkB activation is independent of protein synthesis, and confined to stimulated synapses. Induction of L-LTP by strong stimulation in one synaptic pathway converts weak TBS-induced E-LTP to L-LTP in a second, independent pathway. Transient inhibition of TrkB around the time of weak TBS to the second pathway diminished L-LTP in that pathway without affecting the first one. Behaviorally, weak training, which induces short-term memory (STM) but not LTM, can be consolidated into LTM by exposing animals to novel but not familiar environment 1 h before training. Inhibition of TrkB during STM training blocked such consolidation. These results suggest TrkB as a potential tag for synapse-specific expression of L-LTP and LTM.

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Available from: Robert Schloesser, Oct 03, 2015
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    • "CFC, contextual fear conditioning. been shown to be potential behavioral tags (Lu et al., 2011; Moncada et al., 2011; de Carvalho Myskiw et al., 2014). In particular, BDNF is sufficient to induce the transformation of early-LTP into late-LTP, suggesting that BDNF signaling is involved in synaptic tagging (Rex et al., 2007). "
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    ABSTRACT: Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction. Copyright © 2015 the authors 0270-6474/15/358308-14$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2015; 35(21):8308-21. DOI:10.1523/JNEUROSCI.0005-15.2015 · 6.34 Impact Factor
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    • "Post-translational events in which plasticity-related proteins (PRPs) modify synapses, thereby completing the E-T circuit, are currently the focus of intensive research. One model suggests that molecular " tags " – possibly tyrosine kinase B (TrkB) – localized at presynaptic terminals – recruit PRPs during memory stabilization (Frey and Morris, 1997; Lisman and Raghavachari, 2006; Lu et al., 2011). Simultaneously, upregulated ␣-amino-3-hydroxy-5- methyl-4-isoxazoleproprionic receptors (AMPARs) are anchored to the postsynaptic density (PSD) via a pool of PRPs. "
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    ABSTRACT: Neurologically-complex species utilize two intricately-coupled information–processing systems to adapt to their social and natural environments. Action potentials (APs) facilitate rapid responses to the nearly continuous fluctuations in the animal's surroundings. By contrast, genetic encodings comprise a molecular memory of ancient adaptive responses expressed as cognitive, emotional, or behavioral phenotypes. The linking of the two systems via intracellular Ca2+ networks which address transcription factors---e.g., cAMP response element-binding protein (CREB)---is an appropriate focus for the biology of human behavior. Computational modeling utilizing Boolean networks (BNs) is a suitable qualitative method, requiring no kinetic information, for eliciting the systems’ architectural properties. In particular, BNs can reveal critical intracellular regimes of possible evolutionary significance. As a platform for future research, we propose that those networks sufficiently robust to attenuate damaging intracellular noise and deleterious mutations, yet sufficiently close to chaos to permit or amplify adaptive noise and favorable mutations, would be favored by natural selection. Critical regimes of this type would be, literally, “poised for survival”, and would stabilize and promote the survival of their correlated cultural phenotypes.
    The International Journal of Biochemistry & Cell Biology 01/2015; 61. DOI:10.1016/j.biocel.2015.01.013 · 4.05 Impact Factor
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    • "Moreover, blockade of BDNF signaling immediately following LTP induction reduced LTP persistence. Specifically, LTP induction in slices generated a transient peak in the phosphorylated form of the TrkB receptor for BDNF; pTrkB levels rose 15 min following induction, peaked at 30 min, and slowly declined to baseline over 2 h (Lu et al., 2011). Preventing TrkB activation with TrkB-IgG at the 30-min peak, but not at 60 min post-induction, inhibited persistent LTP (Kang et al., 1997). "
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    ABSTRACT: Memories are dynamic physical phenomena with psychometric forms as well as characteristic timescales. Most of our understanding of the cellular mechanisms underlying the neurophysiology of memory, however, derives from one-trial learning paradigms that, while powerful, do not fully embody the gradual, representational, and statistical aspects of cumulative learning. The early olfactory system-particularly olfactory bulb-comprises a reasonably well-understood and experimentally accessible neuronal network with intrinsic plasticity that underlies both one-trial (adult aversive, neonatal) and cumulative (adult appetitive) odor learning. These olfactory circuits employ many of the same molecular and structural mechanisms of memory as, for example, hippocampal circuits following inhibitory avoidance conditioning, but the temporal sequences of post-conditioning molecular events are likely to differ owing to the need to incorporate new information from ongoing learning events into the evolving memory trace. Moreover, the shapes of acquired odor representations, and their gradual transformation over the course of cumulative learning, also can be directly measured, adding an additional representational dimension to the traditional metrics of memory strength and persistence. In this review, we describe some established molecular and structural mechanisms of memory with a focus on the timecourses of post-conditioning molecular processes. We describe the properties of odor learning intrinsic to the olfactory bulb and review the utility of the olfactory system of adult rodents as a memory system in which to study the cellular mechanisms of cumulative learning.
    Frontiers in Behavioral Neuroscience 07/2014; 8:238. DOI:10.3389/fnbeh.2014.00238 · 3.27 Impact Factor
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