Memory retention--the synaptic stability versus plasticity dilemma

Memory maintenance is widely believed to involve long-term retention of the synaptic weights that are set within relevant neural circuits during learning. However, despite recent exciting technical advances, it has not yet proved possible to confirm experimentally this intuitively appealing hypothesis. Artificial neural networks offer an alternative methodology as they permit continuous monitoring of individual connection weights during learning and retention. In such models, ongoing alterations in connection weights are required if a network is to retain previously stored material while learning new information. Thus, the duration of synaptic change does not necessarily define the persistence of a memory; rather, it is likely that a regulated balance of synaptic stability and synaptic plasticity is required for optimal memory retention in real neuronal circuits.     

Stress,synaptic plasticity,and psychopathology

It is now generally recognized that stressful events play a critical role in the genesis of psychopathology. The neurobiological mechanisms that mediate the contribution of stressful events to the manifestation of psychiatric disorders may include changes in synaptic efficacy in different brain areas. Numerous studies in animals have begun to identify some of these areas through experiments manipulating stressful components. This review focuses on alterations of synaptic efficacy in the hippocampus, the lateral septum, and the medial prefrontal cortex that mimic the pathophysiology of depression and post-traumatic stress disorder.     

Estrogens and synaptic plasticity

Estrogens influence morphology of the brain not only in structures linked to reproductive cycle and reproductive behavior but also structure engaged in memory and cognitive functions. Estrogens stimulate synaptogenesis in pyramidal neurons of CA1 field of hippocampus. Increase in the number of spines on apical dendrites in rats occurs in the prostures phase of the cycle as well as exogenous estradiol application in ovariectomized females. The new synapses are enriched in NMDA receptor and it was found that their generation involves activation of NMDA receptors, PKA and CREB. Estradiol-induced synaptogenesis is accompanied by facilitation of LTP induction. Estradiol affects pyramidal cells of CA1 probably by inhibiting GABA-ergic interneurons. It also modulates unspecific activatory systems, which contribute significantly to neuroplasticity.     

Lithium and synaptic plasticity

Lithium, a small cation, has been used in the treatment of bipolar disorders since its introduction in the 1950s by John Cade. Extensive research on the mechanism of action of lithium has revealed several possible targets. For some time, the most widely accepted action of lithium was its inhibitory effect on the synthesis of inositol, resulting in depletion of inositol with profound effects on neuronal signal transduction pathways. However, several studies show that some effects of lithium are not mediated through inositol depletion. Recent findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase highly expressed in the central nervous system. Interestingly, inhibition of GSK-3β has been shown to regulate neuronal plasticity by inducing axonal remodelling and increasing the levels of synaptic proteins. These findings raise the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.     

Spine architecture and synaptic plasticity

Many forms of mental retardation and cognitive disability are associated with abnormalities in dendritic spine morphology. Visualization of spines using live-imaging techniques provides convincing evidence that spine morphology is altered in response to certain forms of LTP-inducing stimulation. Thus, information storage at the cellular level appears to involve changes in spine morphology that support changes in synaptic strength produced by certain patterns of synaptic activity. Because the structure of a spine is determined by its underlying actin cytoskeleton, there has been much effort to identify signaling pathways linking synaptic activity to control of actin polymerization. This review, part of the TINS Synaptic Connectivity series, discusses recent studies that implicate EphB and NMDA receptors in the regulation of actin-binding proteins through modulation of Rho family small GTPases.     

Modulation of synaptic delay during synaptic plasticity

At most synapses, information about the processes underlying transmitter release evoked by a presynaptic action potential has been gathered indirectly, based on characterization of the postsynaptic response. Traditionally, the two electrophysiological parameters used for this indirect investigation are the amplitude and latency of the response. The amplitude measures amount of transmitter released; the latency (synaptic delay) reflects the kinetics of a sequence of events that culminates in release. The latency distribution of quantal events, or the time course of composite evoked responses, can be used to infer the time course of the elevated release probability following a stimulus. Recent studies have demonstrated that synaptic delay is not invariant, but is modifiable during several forms of short-term synaptic plasticity. This suggests that the step of transmitter secretion can be modulated directly. Several models for short-term synaptic plasticity are evaluated in the context of the observed changes in synaptic delay.     

Wdfy3 regulates glycophagy,mitophagy, and synaptic plasticity

Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3’s role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3’s role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.     

Stimulus frequency,calcium levels and striatal synaptic plasticity

Electrophysiological and microfluorimetric measurements were combined to correlate the changes in intracellular calcium concentration to synaptic plasticity in striatal medium spiny projection neurons, during three different protocols of synaptic stimulation (1, 10, and 100 Hz). The 1 Hz stimulation protocol did not cause significant changes either in excitatory postsynaptic potential amplitude or in intracellular calcium concentration. The 10 Hz stimulation protocol induced a moderate increase of intracellular calcium without significantly affecting the excitatory postsynaptic potential amplitude. During the high frequency stimulation large, transient intracellular calcium elevations were recorded, and a significant long-term depression of excitatory postsynaptic potential was achieved. These results suggest that the induction of long-term depression required large, transient increases in intracellular calcium concentration.     

Sensing and expressing homeostatic synaptic plasticity

Chronic changes in the level of neuronal activity (over a period of days) trigger compensatory changes in synaptic function that seem to contribute to the homeostatic restoration of neuronal activity. Changes in both quantal amplitude and vesicle release contribute to homeostatic synaptic plasticity, but they are often considered as the same phenomenon. In this review, we propose a new approach to studying how neuronal activity is sensed and changes in synaptic function are expressed during synaptic compensation. Changes in quantal amplitude and vesicle release should be considered separately in an attempt to identify the sensors that trigger homeostatic synaptic plasticity. Although data are limited, current evidence suggests that the sensors triggering changes in the quantal amplitude and vesicle release exist at different locations. Furthermore, it is important to recognize that at least two different mechanisms underlie changes in quantal amplitude during homeostatic synaptic plasticity: changes in both the number of postsynaptic receptors and loading of synaptic vesicles with neurotransmitter. Finally, modulation of the probability of neurotransmitter release contributes to the changes in vesicle release associated with homeostatic synaptic plasticity. An improved understanding of where and how neuronal activity is sensed, in addition to the types of changes in synaptic function that are induced, will be needed both to design future experiments and to understand the consequences of synaptic compensation following injury to the nervous system.     

Lipid signaling and synaptic plasticity.

Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.     

Regenerative dendritic spikes and synaptic plasticity

During the last decade, our vision of the neuronal dendritic tree has changed from a simple input device conducting afferent input as a passive cable to the cell soma to a series of independent and actively operating processing units. Different voltage- and ligand-gated ion channels located in the dendritic tree not only participate in processing afferent inputs but also enable the dendritic tree to initiate regenerative spikes, traditionally considered to be exclusively restricted to axonal structures. Recent results suggest that these local dendritic spikes may act as a means to initiate long-term synaptic plasticity. Different from Hebbian synaptic plasticity this type of induction does not need axonal action potential firing and backpropagation into the dendrite. This new proximity learning rule, first postulated by neural network theorists, may have large significance for the information processing in the brain.     

Thalamocortical synaptic connections: efficacy, modulation, inhibition and plasticity

The thalamic input to the neocortex is communicated by glutamatergic synapses. The properties and organization of these synapses determine the primary level of cortical processing. Similar to intracortical synapses, both AMPA and NMDA receptors in young and mature animals mediate thalamocortical transmission. Kainate receptors participate in thalamocortical transmission during early development. The shape of thalamocortical synaptic potentials is similar to the shape of intracortical potentials. On the other hand, thalamocortical synapses have on average a higher release probability than intracortical synapses, and a much higher number of release sites per axon. As a result, the transmission of each thalamocortical axon is significantly more reliable and efficient than most intracortical axons. Thalamic axons specifically innervate a subset of inhibitory cells, to create a strong and secure feed-forward inhibitory pathway. Thalamocortical connections display many forms of synaptic plasticity in the first postnatal week, but not afterwards. The implications of the functional organization of thalamocortical synapses for neocortical processing are discussed.     

Integrin-mediated regulation of synaptic morphology, transmission, and plasticity.

Volado, the gene encoding the Drosophila alphaPS3-integrin, is required for normal short-term memory formation (Grotewiel et al., 1998), supporting a role for integrins in synaptic modulation mechanisms. We show that the Volado protein (VOL) is localized to central and peripheral larval Drosophila synapses. VOL is strongly concentrated in a subpopulation of synaptic boutons in the CNS neuropil and to a variable subset of synaptic boutons at neuromuscular junctions (NMJs). Mutant morphological and functional synaptic phenotypes were analyzed at the NMJ. Volado mutant synaptic arbors are structurally enlarged, suggesting VOL negatively regulates developmental synaptic sprouting and growth. Mutant NMJs exhibit abnormally large evoked synaptic currents and reduced Ca(2+) dependence of transmission. Strikingly, multiple forms of Ca(2+)- and activity-dependent synaptic plasticity are reduced or absent. Conditional Volado expression in mutant larvae largely rescues normal transmission and plasticity. Pharmacologicially disrupting integrin function at normal NMJs phenocopies features of mutant transmission and plasticity within 30-60 min, demonstrating that integrins acutely regulate functional transmission. Our results provide direct evidence that Volado regulates functional synaptic plasticity processes and support recent findings implicating integrins in rapid changes in synaptic efficacy and in memory formation.     

Triggers and substrates of hippocampal synaptic plasticity

It is widely assumed that behavioral learning reflects adaptive properties of the neuronal networks underlying behavior. Adaptive properties of networks in turn arise from the existence of biochemical mechanisms that regulate the efficacy of synaptic transmission. Considerable progress has been made in the elucidation of the mechanisms involved in synaptic plasticity at central synapses and especially those responsible for the phenomenon of long-term potentiation (LTP) of synaptic transmission in hippocampus. While the nature and the timing requirements of the triggering steps are reasonably well known, there is still a lot of uncertainty concerning the mechanisms responsible for the long-term changes. Several biochemical processes have been proposed to play critical roles in promoting long-lasting modifications of synaptic efficacy. This review examines first the triggers that are necessary to produce LTP in the hippocampus and then the different biochemical processes that have been considered to participate in the maintenance of LTP. Finally, we examine the relationships between LTP and behavioral learning.     

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-β-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease.     

Structural and synaptic plasticity in stress-related disorders

Abstract Stress can have a lasting impact on the structure and function of brain circuitry that results in long-lasting changes in the behavior of an organism. Synaptic plasticity is the mechanism by which information is stored and maintained within individual synapses, neurons, and neuronal circuits to guide the behavior of an organism. Although these mechanisms allow the organism to adapt to its constantly evolving environment, not all of these adaptations are beneficial. Under prolonged bouts of physical or psychological stress, these mechanisms become dysregulated, and the connectivity between brain regions becomes unbalanced, resulting in pathological behaviors. In this review, we highlight the effects of stress on the structure and function of neurons within the mesocorticolimbic brain systems known to regulate mood and motivation. We then discuss the implications of these spine adaptations on neuronal activity and pathological behaviors implicated in mood disorders. Finally, we end by discussing recent brain imaging studies in human depression within the context of these basic findings to provide insight into the underlying mechanisms leading to neural dysfunction in depression.     

Cognition and synaptic plasticity in diabetes mellitus

Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits are paralleled by neurophysiological and structural changes in the brain. In animal models of diabetes, impairments of spatial learning occur in association with distinct changes in hippocampal synaptic plasticity. At the molecular level these impairments might involve changes in glutamate-receptor subtypes, in second-messenger systems and in protein kinases. The multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood, but clearly shares features with brain ageing and the pathogenesis of diabetic neuropathy. It involves both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. Treatment with insulin might therefore not only correct hyperglycaemia, but could also directly affect the brain.