Learning-related synaptic plasticity: LTP and LTD.

The past several years have seen studies of synaptic plasticity in both invertebrate and vertebrate nervous systems come of age and lead to important new findings. In particular, current evidence points to a possible presynaptic site for long-term potentiation and the involvement of a retrograde messenger from the postsynaptic neuron. Recent advances in both cerebellar and cortical forms of long-term depression are also discussed.     

Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory

Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap and underscores the functional importance of this regulation in homeostatic synaptic plasticity.     

Diffusion MRI of structural brain plasticity induced by a learning and memory task

Background

Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long-term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood.

Methodology/Principal Finding

Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus.

Conclusion/Significance

We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP.     

Time scales of memory, learning, and plasticity

After only about 10 days would the storage capacity of our nervous system be reached if we stored every bit of input. The nervous system relies on at least two mechanisms that counteract this capacity limit: compression and forgetting. But the latter mechanism needs to know how long an entity should be stored: some memories are relevant only for the next few minutes, some are important even after the passage of several years. Psychology and physiology have found and described many different memory mechanisms, and these mechanisms indeed use different time scales. In this prospect we review these mechanisms with respect to their time scale and propose relations between mechanisms in learning and memory and their underlying physiological basis.     

Dendritic protein synthesis, synaptic plasticity, and memory

Considerable evidence suggests that the formation of long-term memories requires a critical period of new protein synthesis. Recently, the notion that some of these newly synthesized proteins originate through local translation in neuronal dendrites has gained some traction. Here, we review the experimental support for this idea and highlight some of the key questions outstanding in this area.     

Immediate-early genes, neuronal plasticity, and memory.

The demonstration that the immediate-early gene c-fos is rapidly and transiently expressed in brain following a variety of manipulations has led to intense study of these genes to determine what physiological role they play. The very wide range of stimuli which lead to induction of immediate-early genes (IEGs) in the brain has raised concerns for the specificity of their actions and the suggestion that they might merely be involved in housekeeping functions. On the other hand, there is evidence that these genes may play a role in the transmission of information from cell surface receptors to the genetic material in many instances of neuronal plasticity, including development of seizure susceptibility (kindling), long-term potentiation, drug-induced changes, the phase shift in circadian rhythms, and spreading neuronal depression. In addition to being a putative third (or fourth) messenger involved in transduction of signals to the genetic material, activation of IEGs has proven to be a useful tool for the study of transsynaptic activation of certain neuronal pathways in the brain. Thus, studies on the induction of IEGs are proving to be especially useful in understanding some important functions and properties of the mammalian brain.     

Impact of active dendrites and structural plasticity on the memory capacity of neural tissue

We consider the combined effects of active dendrites and structural plasticity on the storage capacity of neural tissue. We compare capacity for two different modes of dendritic integration: (1) linear, where synaptic inputs are summed across the entire dendritic arbor, and (2) nonlinear, where each dendritic compartment functions as a separately thresholded neuron-like summing unit. We calculate much larger storage capacities for cells with nonlinear subunits and show that this capacity is accessible to a structural learning rule that combines random synapse formation with activity-dependent stabilization/elimination. In a departure from the common view that memories are encoded in the overall connection strengths between neurons, our results suggest that long-term information storage in neural tissue could reside primarily in the selective addressing of synaptic contacts onto dendritic subunits.     

Dendritic structural plasticity

Dendrites represent the compartment of neurons primarily devoted to collecting and computating input. Far from being static structures, dendrites are highly dynamic during development and appear to be capable of plastic changes during the adult life of animals. During development, it is a combination of intrinsic programs and external signals that shapes dendrite morphology; input activity is a conserved extrinsic factor involved in this process. In adult life, dendrites respond with more modest modifications of their structure to various types of extrinsic information, including alterations of input activity. Here, the author reviews classical and recent evidence of dendrite plasticity in invertebrates and vertebrates and current progress in the understanding of the molecular mechanisms that underlie this plasticity. Importantly, some fundamental questions such as the functional role of dendrite remodeling and the causal link between structural modifications of neurons and plastic processes, including learning, are still open.     

Ubiquitous plasticity and memory storage

To date, most hypotheses of memory storage in the mammalian brain have focused upon long-term synaptic potentiation and depression (LTP and LTD) of fast glutamatergic excitatory postsynaptic currents (EPSCs). In recent years, it has become clear that many additional electrophysiological components of neurons, from electrical synapses to glutamate transporters to voltage-sensitive ion channels, can also undergo use-dependent long-term plasticity. Models of memory storage that incorporate this full range of demonstrated electrophysiological plasticity are better able to account for both the storage of memory in neuronal networks and the complexities of memory storage, indexing, and recall as measured behaviorally.     

mRNA at synapses,synaptic plasticity,and memory consolidation

Miller et al. (this issue of Neuron) report that deletion of the 3'UTR of alpha-CaMKII mRNA prevents dendritic delivery of the mRNA in transgenic mice and thus local synthesis of alpha-CaMKII protein in dendrites. 3'UTR mutant mice exhibit decreases in alpha-CaMKII protein in postsynaptic densities, and deficits in late phase LTP and in memory consolidation.     

Trans-synaptic plasticity: presynaptic initiation, postsynaptic memory

A novel mechanism of persistent facilitation induced by serotonin at Aplysia synapses depends upon rapid postsynaptic protein synthesis and increased responsiveness to glutamate; whereas the memory for this synaptic change is postsynaptic, the initiating signal may be an increase in spontaneous release of glutamate from the presynaptic terminals.     

Calcineurin in memory and bidirectional plasticity

The molecular mechanisms of learning and memory, and the underlying bidirectional changes in synaptic plasticity that sustain them largely implicate protein kinases and phosphatases. Specifically, Ca(2+)-dependent kinases and phosphatases actively control neuronal processing by forming a tightly regulated balance in which they oppose each other. In this balance, calcineurin (PP2B) is a critical protein phosphatase whose main function is to negatively modulate learning, memory, and plasticity. It acts by dephosphorylating numerous substrates in different neuronal compartments. This review outlines some of CN neuronal targets and their implication in synaptic functions, and describes the role of CN in the acquisition, storage, retrieval, and extinction of memory, as well as in bidirectional plasticity.     

Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with a multitude of functions. Although Cdk5 is widely expressed, it has been studied most extensively in neurons. Since its initial characterization, the fundamental contribution of Cdk5 to an impressive range of neuronal processes has become clear. These phenomena include neural development, dopaminergic function and neurodegeneration. Data from different fields have recently converged to provide evidence for the participation of Cdk5 in synaptic plasticity, learning and memory. In this review, we consider recent data implicating Cdk5 in molecular and cellular mechanisms underlying synaptic plasticity. We relate these findings to its emerging role in learning and memory. Particular attention is paid to the activation of Cdk5 by p25, which enhances hippocampal synaptic plasticity and memory, and suggests formation of p25 as a physiological process regulating synaptic plasticity and memory.     

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

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.     

Geometry and structural plasticity of synaptic connectivity

Changes in synaptic connectivity patterns through the formation and elimination of dendritic spines may contribute to structural plasticity in the brain. We characterize this contribution quantitatively by estimating the number of different synaptic connectivity patterns attainable without major arbor remodeling. This number depends on the ratio of the synapses on a dendrite to the axons that pass within a spine length of that dendrite. We call this ratio the filling fraction and calculate it from geometrical analysis and anatomical data. The filling fraction is 0.26 in mouse neocortex, 0.22-0.34 in rat hippocampus. In the macaque visual cortex, the filling fraction increases by a factor of 1.6-1.8 from area V1 to areas V2, V4, and 7a. Since the filling fraction is much smaller than 1, spine remodeling can make a large contribution to structural plasticity.     

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.     

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.