Mechanisms of synaptic plasticity

We have shown that the synapse maturation phase of synaptogenesis is a model for synaptic plasticity that can be particularly well-studied in chicken forebrain because for most forebrain synapses, the maturation changes occur slowly and are temporally well-separated from the synapse formation phase. We have used the synapse maturation phase of neuronal development in chicken forebrain to investigate the possible link between changes in the morphology and biochemical composition of the postsynaptic density (PSD) and the functional properties of glutamate receptors overlying the PSD. Morphometric studies of PSDs in forebrains and superior cervical ganglia of chickens and rats have shown that the morphological features of synapse maturation are characteristic of a synaptic type, but that the rate at which these changes occur can vary between types of synapses within one animal and between synapses of the same type in different species. We have investigated, during maturation in the chicken forebrain, the properties of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors, which are concentrated in the junctional membranes overlying thick PSDs in the adult. There was no change in the number of NMDA receptors during maturation, but there was an increase in the rate of NMDA-stimulated uptake of 45Ca2+ into brain prisms. This functional change was not seen with the other ionotropic subtypes of the glutamate receptor and was NMDA receptor-mediated. The functional change also correlated with the increase in thickness of the PSD during maturation that has previously been shown to be due to an increase in the amount of PSD associated Ca(2+)-calmodulin stimulated protein kinase II (CaM-PK II). Our results provide strong circumstantial evidence for the regulation of NMDA receptors by the PSD and implicate changing local concentrations of CaM-PK II in this process. The results also indicate some of the ways in which properties of existing synapses can be modified by changes at the molecular level.     

Mechanisms of neural plasticity following brain injury

Brain insults cause rapid cell death, and a disruption of functional circuits, in the affected regions. As the injured tissue recovers from events associated with cell death, regenerative processes are activated that over months lead to a certain degree of functional recovery. Factors produced by new neurons and glia, axonal sprouting of surviving neurons, and new synapse formation help to re-establish some of the lost functions. The timing and location of such events is crucial in the success of the regenerative process. Comprehensive gene expression profiling and proteomic analyses have enabled a deeper molecular and cellular mechanistic understanding of post-injury brain regeneration. These new mechanistic insights are aiding the design of novel therapeutic modalities that enhance regeneration.     

Mechanisms and significance of spike-timing dependent plasticity

Hebb's original postulate left two important issues unaddressed: (i) what is the effective time window between pre- and postsynaptic activity that will result in potentiation? and (ii) what is the learning rule that underlies decreases in synaptic strength? While research over the past 2 decades has addressed these questions, several studies within the past 5 years have shown that synapses undergo long-term depression (LTD) or long-term potentiation (LTP) depending on the order of activity in the pre- and postsynaptic cells. This process has been referred to as spike-timing dependent plasticity (STDP). Here we discuss the experimental data on STDP, and develop models of the mechanisms that may underlie it. Specifically, we examine whether the standard model of LTP and LTD in which high and low levels of Ca(2+) produce LTP and LTD, respectively, can also account for STDP. We conclude that the standard model can account for a type of STDP in which, counterintuitively, LTD will be observed at some intervals in which the presynaptic cell fires before the postsynaptic cell. This form of STDP will also be sensitive to parameters such as the presence of an after depolarization following an action potential. Indeed, the sensitivity of this type of STDP to experimental parameters suggests that it may not play an important physiological role in vivo. We suggest that more robust forms of STDP, which do not exhibit LTD at pre-before-post intervals, are not accounted for by the standard model, and are likely to rely on a second coincidence detector in addition to the NMDA receptor.     

Mechanisms controlling axonal sprouting at the neuromuscular junction

This review considers the relative roles of sprouting stimuli, perisynaptic Schwann cells and neuromuscular activity in axonal sprouting at the neuromuscular junction in partially denervated muscles. A number of sprouting stimuli, including insulin-like growth factor II, which are generated from inactive muscle fibers in partially denervated and paralyzed skeletal muscles, has been considered. There is also evidence that perisynaptic Schwann cells induce and guide axonal sprouting in adult partially denervated muscles. Excessive neuromuscular activity significantly reduces bridging of perisynaptic Schwann cell processes between innervated and denervated endplates and thereby inhibits axonal sprouting in partially denervated adult muscles. Elimination of neuromuscular activity is also detrimental to sprouting in these muscles, suggesting that calcium influx into the nerve is crucial for axonal sprouting. The role of neuromuscular activity in axonal sprouting will be considered critically in the context of the roles of sprouting stimuli and perisynaptic Schwann cells in the process of axonal sprouting.     

The role of Nogo-A in axonal plasticity, regrowth and repair

Axonal damage leads to permanent deficits in the adult central nervous system (CNS) not only because of the weak intrinsic ability of adult neurons to activate their growth program but importantly also because of the presence of specific growth inhibitors in the CNS tissue and the environment of the damaged axons. The well-studied myelin-derived protein Nogo-A is involved in various cellular and molecular events contributing to the failure of CNS axons to regrow and reconnect after transection. Recent studies have shown that, by acting in a negative way on the cytoskeleton and on the growth program of axotomized neurons, Nogo-A exerts fast and chronic inhibitory effects on neurite outgrowth. On the other hand, the blockade of Nogo-A results in a marked enhancement of compensatory and regenerative axonal extension in vivo; this enhancement is often paralleled by significant functional recovery, for example, of locomotion or skilled forelimb reaching after spinal cord or stroke lesions in rats and monkeys. Surprisingly, the blockade of Nogo-A or its receptor NgR in the hippocampus has recently been demonstrated to enhance long-term potentiation. A role of Nogo-A in synaptic plasticity/stability might therefore represent an additional, new and important aspect of CNS circuit remodeling. Function-blocking anti-Nogo-A antibodies are currently being tested in a clinical trial for improved outcome after spinal cord injury.     

Mechanisms of long-term plasticity of hippocampal GABAergic synapses

Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABA_B and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The preand postsynaptic effects of activation of these receptors are also discussed.     

Invited review: Mechanisms underlying motor unit plasticity in the respiratory system.

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the function of the motor unit (comprising an individual motoneuron and the muscle fibers it innervates). Considerable diversity exists across diaphragm motor units, yet remarkable homogeneity is present (and maintained) within motor units. In recent years, the mechanisms underlying the development and adaptability of respiratory motor units have received great attention, leading to significant advances in our understanding of diaphragm motor unit plasticity. For example, following imposed inactivity of the diaphragm muscle, there are changes at phrenic motoneurons, neuromuscular junctions, and muscle fibers that tend to restore the ability of the diaphragm to sustain ventilation. The role of activity, neurotrophins, and other growth factors in modulating this adaptability is discussed.     

Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex

We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1-150 microm over 4 days; approximately 5% of total axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month approximately 85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month approximately 40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of axonal branches and boutons contributes to the remodeling of specific functional circuits.     

Mechanisms controlling assembly and plasticity of presynaptic active zone scaffolds

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昆虫翅型分化的表型可塑性机制

翅多型现象在昆虫中广泛存在,是昆虫在飞行扩散和繁殖能力之间权衡的一种策略,对种群的环境适应性进化具有重要的意义。目前在植食性昆虫中研究较多,有关寄生蜂的翅型分化鲜见报道。综述了昆虫翅型分化的表型可塑性机制。遗传因素和环境因素均对昆虫翅的发育产生影响,基因型对翅型的决定具有显著作用,外界环境条件,包括温度、光周期、食物质量、自身密度、外源激素等因素对昆虫翅的发育也产生重要的调节作用,从而产生翅的非遗传多型性现象。此外,天敌的寄生或捕食作用可能会诱导某些昆虫的翅型产生隔代表型变化。对昆虫产生翅多型现象的生态学意义及其在生物进化过程中的作用进行了讨论,并探讨了寄生性昆虫翅型分化机制在生物防治上的可能应用途径。功能基因组学和表观遗传学的进一步发展可望为彻底揭示昆虫翅型分化机制提供新的机遇和技术手段。     

Mechanisms of synaptic plasticity: from membrane to intracellular AMPAR trafficking

Brief periods of repetitive neural firing onto adjacent neurons can lead to changes in synaptic plasticity, that is, changes in the make-up of macromolecular complexes located at synapses. This process includes the regulated trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) to synaptic membranes. Little is known, however, about how the AMPARs are regulated before they are shuttled to the membrane. Greger et al. have found that the length of the cytoplasmic tails of constituent subunits of a given AMPAR is determined by editing [at a glutamine (Q) or an arginine (R) codon] near their C termini. Tail length, in turn, dictates whether AMPARs will be retained or quickly released from the endoplasmic reticulum.     

Slow axonal transport.

New studies provide further evidence that the neuronal cytoskeleton is the product of a dynamic interplay between axonal transport processes and locally regulated assembly mechanisms. These data confirm that the axonal cytoskeleton in mammalian systems is largely stationary and is maintained by a smaller pool of moving subunits or polymers. Slow axonal transport in certain lower species, however, may exhibit quite different features.