Protein kinase signaling in synaptic plasticity and memory

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.     

Lipid signaling: sleep, synaptic plasticity, and neuroprotection

Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175; Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance. Proc Natl Acad Sci USA 1995; 92:5047; Chen C, Magee CJ, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87:2851]. Recently, we found that prolonged continuous wakefulness (primarily rapid eye movement (REM)-sleep deprivation, SD) causes impairments in hippocampal long-term synaptic plasticity and hippocampus-dependent memory formation [McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 2003; 23:9687]. To explore the mechanisms underlying SD-induced impairments, we have studied several bioactive lipids in the hippocampus following SD. It appears that SD causes increases in prostaglandin D2 (PGD2) and 2-arachidonylglycerol (2-AG), and a decrease in PGE2, suggesting that these lipid messengers participate in memory consolidation during REM sleep. We have also explored the formation of endogenous neuroprotective lipids. Toward this aim, we have used ischemia-reperfusion damage and LC-PDA-ESI-MS-MS-based lipidomic analysis and identified docosanoids derived from synaptic phospholipid-enriched docosahexaenoic acid. Some of the docosanoids exert potent neuroprotective bioactivity [Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003; 278:43807; Mukherjee PK, Marcheselli VL, Serhan CN, Bazan, NG. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Nat Acad Sci USA 2004; 101:8491). Taken together, these observations that signaling lipids participate in synaptic plasticity, cognition, and survival indicate that lipid signaling is closely associated with several functions (e.g; learning and memory, sleep, and experimental stroke) and pathologic events. Alterations in endogenous signaling lipids or their receptors resulting from drug abuse lead to changes in synaptic circuitry and induce profound effects on these important functions. In the present article, we will briefly review bioactive lipids involved in sleep, synaptic transmission and plasticity, and neuroprotection, focusing mainly on our experimental studies and how these signaling molecules are related to functions and implicated in some neurologic disorders.     

Hebbian plasticity in parallel synaptic pathways: A circuit mechanism for systems memory consolidation

Systems memory consolidation involves the transfer of memories across brain regions and the transformation of memory content. For example, declarative memories that transiently depend on the hippocampal formation are transformed into long-term memory traces in neocortical networks, and procedural memories are transformed within cortico-striatal networks. These consolidation processes are thought to rely on replay and repetition of recently acquired memories, but the cellular and network mechanisms that mediate the changes of memories are poorly understood. Here, we suggest that systems memory consolidation could arise from Hebbian plasticity in networks with parallel synaptic pathways—two ubiquitous features of neural circuits in the brain. We explore this hypothesis in the context of hippocampus-dependent memories. Using computational models and mathematical analyses, we illustrate how memories are transferred across circuits and discuss why their representations could change. The analyses suggest that Hebbian plasticity mediates consolidation by transferring a linear approximation of a previously acquired memory into a parallel pathway. Our modelling results are further in quantitative agreement with lesion studies in rodents. Moreover, a hierarchical iteration of the mechanism yields power-law forgetting—as observed in psychophysical studies in humans. The predicted circuit mechanism thus bridges spatial scales from single cells to cortical areas and time scales from milliseconds to years.     

Information characteristics of neuronal and synaptic plasticity

Informational losses in neuronal nets(NN) with plastic elements were estimated. These losses are related with 1) transition from "complicated" decoding when from the modification state of such elements information of the whole set of recorded elements is extracted to "simple" decoding natural of NN functioning when information is extracted independently for individual events; 2) uncertainty concerning NN structure, if at decoding in one of the modification states the neuron reactivity totally or the weight of plastic synapse equals zero. After the transition from complicated to simple decoding these losses for gradual plasticity are so great that NN with such plasticity has no advantages in informational capacity as compared to the binary one. These losses are absent for plasticity of Olbus type. They are relatively high for neuronal plasticity of Hebb type. For Hebb synapses their value essentially depends on the net parameters.     

The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory

The mitogen-activated protein kinase (MAP kinase, MAPK) cascade, as the name implies, was originally discovered as a critical regulator of cell division and differentiation. As further details of this signaling cascade were worked out, it became clear that the MAPK cascade is in fact a prototype for a family of signaling cascades that share the motif of three serially linked kinases regulating each other by sequential phosphorylation. Thus, a revised nomenclature arose that uses the term MAPK to refer to the entire superfamily of signaling cascades (comprising the erks, the JNKs and the p38 stress activated protein kinases), and specifies the prototype MAPK as the extracellular signal-regulated kinase (erk). The two erk MAPK isoforms, p44 MAPK and p42 MAPK, are referred to as erk1 and erk2, respectively.The erks are abundantly expressed in neurons in the mature central nervous system, raising the question of why the prototype molecular regulators of cell division and differentiation are present in these non-dividing, terminally differentiated neurons. This review will describe the beginnings of an answer to this question. Interestingly, the general model has begun to emerge that the erk signaling system has been co-opted in mature neurons to function in synaptic plasticity and memory. Moreover, recent insights have led to the intriguing prospect that these molecules serve as biochemical signal integrators and molecular coincidence detectors for coordinating responses to extracellular signals in neurons. In this review I will first outline the essential components of this signal transduction cascade, and briefly describe recent results implicating the erks in mammalian synaptic plasticity and learning. I will then proceed to outline recent results implicating the erks as molecular signal integrators and, potentially, coincidence detectors. Finally, I will speculate on what the critical downstream effectors of the erks are in neurons, and how they might provide a readout of the integrated signal.     

Reciprocal interaction of sleep and synaptic plasticity

Synaptic plasticity underlying learning and memory has been proposed, on the basis of several experimental approaches, to be intimately related with sleep: 1) The idea that sleep contributes to stabilization of acquired memory arises from numerous studies depriving subjects or animals of sleep. 2) Evidence from developing technologies supports "offline" reprocessing of recent experiences during sleep. 3) Recent analysis of the thalamocortical system establishes the reciprocal observation that sleep itself is a plastic process affected by waking experience. This overview synthesizes these converging perspectives across a variety of brain regions and species. We propose the developing visual pathway as a fruitful model for comprehensive understanding of sleep and synaptic plasticity.     

神经胶质细胞与突触可塑性研究新进展

突触的可塑性是研究学习与记忆的基础,很长时间以来人们对突触的可塑性研究主要集中在神经元和突触上;而胶质细胞的作用较少受到注意。最近的研究发现胶质细胞也参与突触的构成并影响突触的活动。研究表明中枢神经系统中的胶质细胞包括星形胶质细胞、小胶质细胞和少突胶质细胞可分别通过谷氨酸、丝氨酸、甘氨酸、ATP等信号调节突触的可塑性,从而为突触的可塑性研究提供了新的思路和方向,并有助于阐明突触的发生以及学习与记忆的机制。     

Focal adhesion kinase regulates neuronal growth, synaptic plasticity and hippocampus-dependent spatial learning and memory

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase abundantly expressed in the mammalian brain and highly enriched in neuronal growth cones. Inhibitory and facilitatory activities of FAK on neuronal growth have been reported and its role in neuritic outgrowth remains controversial. Unlike other tyrosine kinases, such as the neurotrophin receptors regulating neuronal growth and plasticity, the relevance of FAK for learning and memory in vivo has not been clearly defined yet. A comprehensive study aimed at determining the role of FAK in neuronal growth, neurotransmitter release and synaptic plasticity in hippocampal neurons and in hippocampus-dependent learning and memory was therefore undertaken using the mouse model. Gain- and loss-of-function experiments indicated that FAK is a critical regulator of hippocampal cell morphology. FAK mediated neurotrophin-induced neuritic outgrowth and FAK inhibition affected both miniature excitatory postsynaptic potentials and activity-dependent hippocampal long-term potentiation prompting us to explore the possible role of FAK in spatial learning and memory in vivo. Our data indicate that FAK has a growth-promoting effect, is importantly involved in the regulation of the synaptic function and mediates in vivo hippocampus-dependent spatial learning and memory.     

Wnt signaling during synaptic development and plasticity

The formation of synaptic connections requires a dialogue between pre and postsynaptic cells to coordinate the assembly of the presynaptic release machinery and the postsynaptic receptive complexes. Signaling molecules of the Wnt family of proteins are central to this trans-synaptic dialogue. At the neuromuscular junction and central synapses, Wnts promote synaptic assembly by signaling to the developing pre and postsynaptic compartments. In addition, new studies reveal that expression of Wnt proteins and localization of their Fz receptors are regulated by neuronal activity. Importantly, Wnts mediates the synaptic changes induced by patterned neuronal activity or sensory experience in mature neurons. Here we review recent findings into the function of Wnt signaling at the synapse and its link to activity-dependent synaptic growth and function.     

Molecular mechanisms of synaptic plasticity and memory.

To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.     

The neuronal death protein par-4 mediates dopaminergic synaptic plasticity

Par-4, discovered in a screen for genes whose expression is increased in prostate tumor cells undergoing apoptosis, participates in physiological and pathological nerve cell death. A new study, however, provides evidence for an unexpected role for Par-4 in regulating synaptic transmission in the brain: Par-4 binds to the D2 dopamine receptor (D2DR) and modulates its activity. Mice in which the function of Par-4 is disrupted exhibit impaired dopaminergic neurotransmission, resulting in a depression-like syndrome. Several other cell death-related proteins also appear to function in regulating synaptic plasticity, suggesting that a better understanding of the functions of these proteins may lead to novel therapeutic approaches for a psychiatric and neurodegenerative disorders.     

Mitogen-activated protein kinases in synaptic plasticity and memory

This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal.     

The role of cell adhesion molecules in synaptic plasticity and memory.

Studies in the past few years suggest that cell adhesion molecules may play signaling as well as structural roles at adult synapses during plasticity. The observation that many adhesion molecules are expressed both pre-synaptically and post-synaptically raises the possibility that information about synaptic activity might simultaneously be communicated to both sides of the synapse, circumventing the need for distinct anterograde and retrograde messengers.