Synaptic Plasticity Consolidation Research Articles

The roles of protein expression in synaptic plasticity and memory consolidation.

The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation.

Dopamine-induced tyrosine phosphorylation of NR2B (Tyr1472) is essential for ERK1/2 activation and processing of novel taste information.

Understanding the heterosynaptic interaction between glutamatergic and neuromodulatory synapses is highly important for revealing brain function in health and disease. For instance, the interaction between dopamine and glutamate neurotransmission is vital for memory and synaptic plasticity consolidation, and it is known to converge on extracellular signal-regulated kinase (ERK)-MAPK signaling in neurons. Previous studies suggest that dopamine induces N-methyl-D-aspartate (NMDA) receptor phosphorylation at the NR2B Y1472 subunit, influencing receptor internalization at the synaptic plasma membrane. However, it is unclear whether this phosphorylation is upstream to and/or necessary for ERK1/2 activation, which is known to be crucial for synaptic plasticity and memory consolidation. Here, we tested the hypothesis that tyrosine phosphorylation of NR2B at Y1472 is correlated with ERK1/2 activation by dopamine and necessary for it as well. We find that dopamine receptor D1, but not D2, activates ERK1/2 and leads to NR2BY1472 phosphorylation in the mature hippocampus and cortex. Moreover, our results indicate that NR2B Y1472 phosphorylation is necessary for ERK1/2 activation. Importantly, application of dopamine or the D1 receptor agonist SKF38393 to hippocampal slices from NR2B F1472 mutant mice did not result in ERK1/2 activation, suggesting this site is not only correlated with ERK1/2 activation by dopamine stimulation, but also necessary for it. In addition, NR2B F1472 mice show impairment in learning of attenuation of taste neophobia but not associative taste learning. Our study shows that the dopaminergic and glutamatergic transmission converge on the NMDA receptor itself, at the Y1472 site of the NR2B subunit, and that this convergence is essential for ERK1/2 activation in the mature brain and for processing new sensory information in the cortex.

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

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.

Reduced basal and novelty-induced levels of activity-regulated cytoskeleton associated protein (Arc) and c-Fos mRNA in the cerebral cortex and hippocampus of APPswe/PS1ΔE9 transgenic mice

Activity-regulated cytoskeletal-associated protein (Arc) and c-Fos are immediate early gene (IEG) products induced by novelty in the hippocampus and involved in the consolidation of synaptic plasticity and long-term memory. We investigated whether induction of arc and c-fos after exposure to a novel open field environment was compromised in different neocortical areas and the hippocampal formation in APP/PS1ΔE9 transgenic mice characterized by pronounced accumulation and deposition of beta amyloid (Aβ). Notably, the basal level of Arc and c-fos mRNA in the neocortex was significantly lower in APP/PS1ΔE9 compared to wild-type mice. Novelty exposure induced an increase in Arc and c-Fos mRNA in the medial prefrontal cortex (mPFC), parietal cortex, and hippocampal formation in both APP/PS1ΔE9 transgenic and wild-type mice. However, novelty-induced IEG expression did not reach the same levels in APP/PS1ΔE9 as in the wild-type mice. In contrast, synaptophysin levels did not differ between mutant and wild type mice, suggesting that the observed effect was not due to a general decrease in the number of presynapses. These data suggest a reduction in basal and novelty-induced neuronal activity in a transgenic mouse model of Alzheimer’s disease, which is most pronounced in cortical regions, indicating that a decreased functional response in IEG expression could be partly responsible for the cognitive deficits observed in patients with Alzheimer’s disease.

AU-rich element-binding protein negatively regulates CCAAT enhancer-binding protein mRNA stability during long-term synaptic plasticity in Aplysia

The consolidation of long-term memory for sensitization and synaptic facilitation in Aplysia requires synthesis of new mRNA including the immediate early gene Aplysia CCAAT enhancer-binding protein (ApC/EBP). After the rapid induction of ApC/EBP expression in response to repeated treatments of 5-hydroxytryptamine (5-HT), ApC/EBP mRNA is temporarily expressed in sensory neurons of sensory-to-motor synapses. However, the molecular mechanism underlying the rapid degradation of ApC/EBP transcript is not known. Here, we cloned an AU-rich element (ARE)-binding protein, ApAUF1, which functions as a destabilizing factor for ApC/EBP mRNA. ApAUF1 was found to bind to the 3' UTR of ApC/EBP mRNA that contains AREs and subsequently reduces the expression of ApC/EBP 3' UTR-containing reporter genes. Moreover, overexpression of ApAUF1 inhibited the induction of ApC/EBP mRNA in sensory neurons and also impaired long-term facilitation of sensory-to-motor synapses by repetitive 5-HT treatments. These results provide evidence for a critical role of the posttranscriptional modification of ApC/EBP mRNA during the consolidation of synaptic plasticity.

Consolidation and translation regulation: Figure 1.

mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is divided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain; both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippocampal-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.

NMDA receptor-independent control of transcription factors and gene expression

Consolidation of synaptic plasticity seems to require transcription, but how the nucleus is informed in this context remains unknown. As NMDA receptor antagonists have been shown to interfere with action potential generation, the issue of whether or not a synaptically generated signal is required for nuclear signaling is currently unresolved. Here, we show that pharmacological maintenance of action potentials during NMDA receptor blockade allows for NMDA receptor-independent transcription factor binding and arc gene expression, both of which were previously thought to be NMDA receptor dependent. These data suggest that types of signaling in the nucleus previously attributed to NMDA-receptor-dependent synapse-to-nucleus signals can be initiated in the absence of NMDA receptor-dependent synaptic plasticity.

Connecting Activity to Endocytosis

Four articles in Neuron provide insight into the function of Arc (also known as Arg3.1, Arc/Arg3.1), which has long been known as a marker for synaptic activity, after which Arc/Arg3.1 mRNA is synthesized and transported to active synapses or is redistributed from inactive to active synapses. These results, along with a review of the Arc/Arg3.1 literature, are discussed by Tzingounis and Nicoll. Using knockout mice, Plath et al . found that loss of Arc/Arg3.1 disrupted long-term memory formation (spatial learning, fear conditioning, conditioned taste aversion, and object recognition), without impairing short-term memory. Analysis of long-term potentiation (LTP) and long-term depression (LTD) in the knockout mice in vivo or in cultured cells showed that the initial phase of LTP was enhanced but the late phase of LTP was inhibited and that LTD was diminished at all times. Shepherd et al . investigated the role of Arc/Arg3.1 in another form of plasticity called homeostatic synaptic scaling. One example of this is the reciprocal changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in response to chronic synaptic activation or synaptic blockade: Numbers of AMPA receptors at the surface increase under conditions of chronic inhibition and decrease under conditions of chronic stimulation. Shepherd et al . found that Arc/Arg3.1 abundance in cultured cortical neurons was inversely correlated with the activity in the cultures: When activity was blocked with tetrodotoxin (TTX), Arc/Arg3.1 abundance decreased, and when activity was enhanced with bicuculline (Bic), Arc/Arg3.1 abundance was increased. Overexpression of Arc/Arg3.1 decreased the abundance of AMPA receptors at the surface and prevented TTX-induced increase in AMPA receptors, blocked the scaling effect, and reduced the amplitude of miniature excitatory postsynaptic currents (mEPSCs). In neurons from Arc/Arg3.1 knockout mice, synaptic scaling in response to either TTX or Bic was completely absent. Thus, from these two studies it appears that Arc/Arg3.1 plays an essential role in Hebbian forms of synaptic plasticity (LTP and LTD) and homeostatic synaptic plasticity and that the mechanism may be regulation of trafficking of AMPA receptors to or from the surface. Rial Verde et al . show that in organotypic hippocampal slices, the abundance of Arc/Arg3.1 correlates inversely with AMPA-mediated activity. Overexpression of Arc/Arg3.1 promoted the endocytosis of AMPA receptors. Chowdhury et al . show that Arc/Arg3.1 interacts with two components of the endocytosis machinery: endophilin and dynamin. The interaction with these proteins was required for overexpressed Arc/Arg3.1 to affect AMPA receptor endocytosis. Thus, Arc/Arg3.1 appears to connect synaptic activity to AMPA receptor endocytosis, which controls the abundance of AMPA receptors at the surface and the AMPA receptor-mediated activity of the synapse. A. V. Tzingounis, R. A. Nicoll, Arc/Arg3.1: Linking gene expression to synaptic plasticity and memory. Neuron 52 , 403-407 (2006). [PubMed] N. Plath, O. Ohana, B. Dammermann, M. L. Errington, D. Schmitz, C. Gross, X. Mao, A. Engelsberg, C. Mahlke, H. Welzl, U. Kobalz, A. Stawrakakis, E. Fernandez, R. Waltereit, A. Bick-Sander, E. Therstappen, S. F. Cooke, V. Blanquet, W. Wurst, B. Salmen, M. R. Bösl, H.-P. Lipp, S. G. N. Grant, T. V. P. Bliss, D. P. Wolfer, D. Kuhl, Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52 , 437-444 (2006). [PubMed] J. D. Shepherd, G. Rumbaugh, J. Wu, S. Chowdhury, N. Plath, D. Kuhl, R. L. Huganir, P. F. Worley, Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52 , 475-484 (2006). [PubMed] E. M. Rial Verde, J. Lee-Osbourne, P. F. Worley, R. Malinow, H. T. Cline, Increased expression of the immediate-early gene Arc/Arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52 , 461-474 (2006). [PubMed] S. Chowdhury, J. D. Shepherd, H. Okuno, G. Lyford, R. S. Petralia, N. Plath, D. Kuhl, R. L. Huganir, P. F. Worley, Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52 , 445-459 (2006). [PubMed]