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.     

Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways

Input-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior.     

Neuronal plasticity and cellular immunity: shared molecular mechanisms

It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.     

The mechanisms of short-term forms of synaptic plasticity

In experiments on the frog cutaneous pectoris muscle in cases of different external calcium concentrations, using extracellular recording technique, processes of facilitation and depression of transmitter release during the high-frequency stimulation were investigated. On the ground of experiments using intracellular mobile calcium buffers BAPTA-AM and EGTA-AM, it was proposed that at least two (low- and high-affinity) calcium-binding sites underlie the facilitation. Both the facilitation and the depression were accompanied by such transformations of underlied of nerve ending responses as changes of the third phase amplitude. Application of potassium channel blockers allowed us to reveal the significant contribution of changes of duration of the AP repolarisation phase and, accordingly, the changes of magnitude of calcium influx to development of facilitation and depression of transmitter release. It was also revealed that, during the high-frequency rhythmic stimulation, the increase of asynchrony of transmitter release leading to decrease of facilitation and increase of depression occurred. It was concluded that the forms of short-term synaptic plasticity--facilitation and depression, were caused by various presynaptic mechanisms: the increase of concentration of "local" and accumulation of "residual" calcium, the changes of calcium influx, increase of temporal course of secretion, the impairment of equilibrium between the depletion and restoration of mediator supply. Due to some of these processes and specific conditions of synapse functioning, the facilitation of the depression of transmitter release occurred.     

Regulatory mechanisms of AMPA receptors in synaptic plasticity

Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.     

Biochemical mechanisms for translational regulation in synaptic plasticity

Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.     

Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function

Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development. Recent work has shown that these destabilizing influences are counterbalanced by homeostatic plasticity mechanisms that act to stabilize neuronal and circuit activity. One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms may allow local changes in synaptic activation to generate local synaptic adaptations, and network-wide changes in activity to generate network-wide adjustments in the balance between excitation and inhibition. The signaling pathways underlying these various forms of homeostatic plasticity are currently under intense scrutiny, and although dozens of molecular pathways have now been implicated in homeostatic plasticity, a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged. On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.     

Novel presynaptic mechanisms for coincidence detection in synaptic plasticity

Long-term plasticity typically relies on postsynaptic NMDA receptors to detect the coincidence of pre- and postsynaptic activity. Recent studies, however, have revealed forms of plasticity that depend on coincidence detection by presynaptic NMDA receptors. In the amygdala, cortical afferent associative presynaptic long-term potentiation (LTP) requires activation of presynaptic NMDA receptors by simultaneous thalamic and cortical afferents. Surprisingly, both types of afferent can also undergo postsynaptically induced NMDA-receptor-dependent LTP. In the neocortex, spike-timing-dependent long-term depression (LTD) requires simultaneous activation of presynaptic NMDA autoreceptors and retrograde signalling by endocannabinoids. In cerebellar LTD, presynaptic NMDA receptor activation suggests that similar presynaptic mechanisms may exist. Recent studies also indicate the existence of presynaptic coincidence detection that is independent of NMDA receptors, suggesting that such mechanisms have a widespread role in plasticity.     

Molecular mechanisms of synaptic specificity in developing neural circuits

The function of the brain depends on highly specific patterns of connections between populations of neurons. The establishment of these connections requires the targeting of axons and dendrites to defined zones or laminae, the recognition of individual target cells, the formation of synapses on particular regions of the dendritic tree, and the differentiation of pre- and postsynaptic specializations. Recent studies provide compelling evidence that transmembrane adhesion proteins of the immunoglobulin, cadherin, and leucine-rich repeat protein families, as well as secreted proteins such as semaphorins and FGFs, regulate distinct aspects of neuronal connectivity. These observations suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of synaptic connections in the developing brain.     

Potential neuronal mechanisms of estrogen actions in synaptogenesis and synaptic plasticity

Summary 1. Studies conducted on the rat arcuate nucleus, an area involved in the development and control of LH and FSH secretion, have shown the existence of hormonally regulated developmental sex differences in synaptic patterns and estrogen-induced synaptic plasticity during adult life. Several questions raised by these findings are examined in this review:2. The mechanisms of estrogen-regulated developmental synaptogenesis. These include the role of glycocalyx glycoproteins in neuronal membranes, neural cell adhesion molecules, and insulin-like growth factor I.3. The relationship among circulating estrogen, gonadotropin levels, and hypothalamic synaptic plasticity. Recent evidence for the role of GABAergic and dopaminergic synaptic inputs and POMC projections from the arcuate nucleus to the GnRH cells is discussed.4. The synaptologic basis of age-related failure of positive feedback. The role of the cumulative effect of repeated preovulatory synaptic retraction and reapplication cycles on sensescent constant estrus is analyzed.     

Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex

As in other mammals with binocular vision, monocular lid suture in mice induces bidirectional plasticity: rapid weakening of responses evoked through the deprived eye followed by delayed strengthening of responses through the open eye. It has been proposed that these bidirectional changes occur through three distinct processes: first, deprived-eye responses rapidly weaken through homosynaptic long-term depression (LTD); second, as the period of deprivation progresses, the modification threshold determining the boundary between synaptic depression and synaptic potentiation becomes lower, favouring potentiation; and third, facilitated by the decreased modification threshold, open-eye responses are strengthened via homosynaptic long-term potentiation (LTP). Of these processes, deprived-eye depression has received the greatest attention, and although several alternative hypotheses are also supported by current research, evidence suggests that alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor endocytosis through LTD is a key mechanism. The change in modification threshold appears to occur partly through changes in N-methyl-D-aspartate (NMDA) receptor subunit composition, with decreases in the ratio of NR2A to NR2B facilitating potentiation. Although limited research has directly addressed the question of open-eye potentiation, several studies suggest that LTP could account for observed changes in vivo. This review will discuss evidence supporting this three-stage model, along with outstanding issues in the field.     

Local learning rules: predicted influence of dendritic location on synaptic modification in spike-timing-dependent plasticity

Recent indirect experimental evidence suggests that synaptic plasticity changes along the dendrites of a neuron. Here we present a synaptic plasticity rule which is controlled by the properties of the pre- and postsynaptic signals. Using recorded membrane traces of back-propagating and dendritic spikes we demonstrate that LTP and LTD will depend specifically on the shape of the postsynaptic depolarization at a given dendritic site. We find that asymmetrical spike-timing-dependent plasticity (STDP) can be replaced by temporally symmetrical plasticity within physiologically relevant time windows if the postsynaptic depolarization rises shallow. Presynaptically the rule depends on the NMDA channel characteristic, and the model predicts that an increase in Mg²⁺ will attenuate the STDP curve without changing its shape. Furthermore, the model suggests that the profile of LTD should be governed by the postsynaptic signal while that of LTP mainly depends on the presynaptic signal shape.     

Presynaptic control of quantal size: kinetic mechanisms and implications for synaptic transmission and plasticity

Although the strength of quantal synaptic transmission is jointly controlled by pre- and post-synaptic mechanisms, the presynaptic mechanisms remain substantially less well characterized. Recent studies reveal that a single package of neurotransmitter is generally insufficient to activate all available postsynaptic receptors, whereas the sum of transmitter from multiple vesicles can result in receptor saturation. Thus, depending upon the number of vesicles released, a given synaptic pathway might be either 'reliable' or 'unreliable'. A lack of receptor saturation in turn makes it possible to modify quantal size by altering the flux of transmitter through the synaptic cleft. Studies are now illuminating several new mechanisms behind the regulation of this transmitter flux--characteristics that control how transmitter is loaded into vesicles, how it is released and the manner by which it interacts with postsynaptic receptors.     

Spatiotemporal profile of N-cadherin expression in the mossy fiber sprouting and synaptic plasticity following seizures

Recurrent seizures can induce mossy fiber sprouting (MFS), of the hippocampal dentate gyrus, and synaptic reorganization in mature brain. This changes local circuits and provides a structural basis for epileptogenesis in the hippocampus. However, the mechanisms of MFS and synaptic reorganization still remain unclear. Neural-cadherin (N-cadherin), a calcium adhesion molecule, plays an important role in neurite outgrowth, pathfinding, and synaptic specificity of early central nervous system development. It is unknown whether N-cadherin is involved in MFS after seizures in mature brain. To further examine the correlation between MFS and N-cadherin expression, we separately labeled MFS and N-cadherin with Timm staining and antibody in adult rats after status epilepticus (SE). Timm staining revealed that MFS is observed in the inner molecular layer of dentate gyrus of rats 2 and 4 weeks after SE. The observed MFS migrated from the hilus to the granule cell layer, gradually extending axons into the inner molecular layer to form an intense band. Immunohistochemical staining of N-cadherin revealed that the upregulated expression of N-cadherin was concentrated in the position of mossy fiber axonal sprouts of rats 1-4 weeks after SE, and that it was earlier than MFS. The spatial and temporal distribution consistence of N-cadherin and Timm staining supported the correlation that exists between N-cadherin expression and the process of aberrant MFS. This result suggests that N-cadherin may be involved in the pathfinding and synaptic specificity of MFS in mature brain after seizures, and can play an important role in the targeted growth of mossy fibers.