Molecular mechanisms of dendritic spine development and remodeling

Dendritic spines are small protrusions that cover the surface of dendrites and bear the postsynaptic component of excitatory synapses. Having an enlarged head connected to the dendrite by a narrow neck, dendritic spines provide a postsynaptic biochemical compartment that separates the synaptic space from the dendritic shaft and allows each spine to function as a partially independent unit. Spines develop around the time of synaptogenesis and are dynamic structures that continue to undergo remodeling over time. Changes in spine morphology and density influence the properties of neural circuits. Our knowledge of the structure and function of dendritic spines has progressed significantly since their discovery over a century ago, but many uncertainties still remain. For example, several different models have been put forth outlining the sequence of events that lead to the genesis of a spine. Although spines are small and apparently simple organelles with a cytoskeleton mainly composed of actin filaments, regulation of their morphology and physiology appears to be quite sophisticated. A multitude of molecules have been implicated in dendritic spine development and remodeling, suggesting that intricate networks of interconnected signaling pathways converge to regulate actin dynamics in spines. This complexity is not surprising, given the likely importance of dendritic spines in higher brain functions. In this review, we discuss the molecules that are currently known to mediate the exquisite sensitivity of spines to perturbations in their environment and we outline how these molecules interface with each other to mediate cascades of signals flowing from the spine surface to the actin cytoskeleton.     

Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling

In the central nervous system, most excitatory synapses occur on dendritic spines, which are small protrusions from the dendritic tree. In the mature cortex and hippocampus, dendritic spines are heterogeneous in shape. It has been shown that the shapes of the spine can affect synapse stability and synaptic function. Dendritic spines are highly motile structures that can undergo actin-dependent shape changes, which occur over a time scale ranging from seconds to tens of minutes or even days. The formation, remodelling and elimination of excitatory synapses on dendritic spines represent ways of refining the microcircuitry in the brain. Here I review the current knowledge on the effects of modulation of AMPA and NMDA ionotropic glutamate receptors on dendritic spine formation, motility and remodelling.     

上腭发生的分子调控机制

哺乳动物上腭的发生包括原生腭和次生腭的发生.其中,次生腭的发生涉及到高度动态的形态发生过程,分为腭突生长及模式化,两侧腭突的上抬/重定位,两侧腭突的黏附和融合形成次生腭等过程.近来的研究表明,上腭发育所需的基因,包括了声波刺猬蛋白(Shh)、成纤维细胞生长因子(FGF)、转化生长因子β(TGF-β)和Wnt信号通路,这...     

脆性X综合征树突棘形态发育研究进展

脆性X综合征(fragile X syndrome,FXS)是X连锁的显性遗传病之一,可导致身体、智力、情感和行为各方面不同程度的改变.该综合征与位于X染色体的FMR-1(fragile mental retardation-1)基因上的三核苷酸基因序列CGG的过度扩增有关.过度扩增导致FMR-1基因甲基化沉默,其编码蛋白FMRP(fragile mental retardation protein)表达下降甚至完全缺失.而FMRP与mRNA共同参与了树突特定mRNA的转运及翻译调控,影响突触的可塑性,从而影响神经系统正常发育.     

Molecular mechanisms guiding late stages of B-cell development

Summary:  In mice, large numbers of immature B cells are continuously produced in the bone marrow. To enter the pools of mature B cells, these immature B cells have to pass two checkpoints. First, B cells have to migrate from the bone marrow to the spleen. The second checkpoint involves the immature B cells differentiating to mature B cells within the spleen. As the net result of this selection and maturation, only a fraction of the newly produced B cells enters the mature B-cell pool. Recent advances in the understanding of the molecular mechanisms that operate at these two checkpoints are described and discussed.     

Molecular mechanisms of development of the gastrointestinal tract.

The gut offers a complex but rich organ system to study visceral pattern formation. The gut is an early evolutionary advance. Data supports that the molecular controls of gut pattern formation are be conserved across species. The gut develops in a stereotyped manner in many different species, by using a basic mechanism of development, the epithelial-mesenchymal interaction. Signaling between the endoderm and mesoderm is essential for normal gut development. The signaling molecules involved are just being described and include factors known to be critical in embryonic development of other systems. The gut has four major patterned axes: anterior-posterior (AP), dorsal-ventral (DV), left-right (LR), and radial (RAD). The molecular pathways used to control pattern in each of these axes are the subject of this review. Major advances in the understanding of AP and LR axis formation in the gut have been described within the past few years. RAD and DV axes are now hot topics for investigation. Despite advances in these areas of gut development, basic events remain poorly understood. Discovery of specific factors that control gut pattern formation may provide a template for the study of pattern formation in other visceral/organ systems.     

Dendrite and dendritic spine alterations in Alzheimer models

Synaptic damage and loss are factors that affect the degree of dementia experienced in Alzheimer disease (AD) patients. Multicolor DiOlistic labeling of the hippocampus has been undertaken which allows the full dendritic arbor of targeted neurons to be imaged. Using this labeling technique the neuronal morphology of two transgenic mouse lines (J20 and APP/PS1) expressing mutant forms of the Amyloid Precursor Protein (APP), at various ages, have been visualized and compared to Wild Type (WT) littermate controls. Swollen bulbous dystrophic neurites with loss of spines were apparent in the transgenic animals. Upon quantification, statistically significant reductions in the number of spines and total dendrite area was observed in both transgenic mouse lines at 11 months of age. Similar morphological abnormalities were seen in human AD hippocampal tissue both qualitatively and quantitatively. Immunohistochemistry and DiOlistic labeling was combined so that Abeta plaques were imaged in relation to the dendritic trees. No preferential localization of these abnormal dystrophic neurites was seen in regions with plaques. DiI labeled reative astrocytes were often apparent in close proximity to A beta plaques.     

Computational study of an excitable dendritic spine

1. A compartmental model was employed to investigate the electrical behavior of a dendritic spine having excitable membrane at the spine head. Here we used the Hodgkin and Huxley equations to generate excitable membrane properties; in some cases the kinetics were modified to get a longer duration action potential. Passive membrane was assumed for both the spine stem and the dendritic shaft. Synaptic input was modeled as a transient conductance increase (alpha-function) that lies in series with a battery (that corresponds to an excitatory or inhibitory synaptic equilibrium potential). 2. Threshold conditions for an action potential at the spine head membrane were found to be sensitive to the membrane properties at the spine head and to the conductance loading provided by the spine stem and the dendritic tree. Increasing either the number or the open times of the excitable channels had the effect of lowering spike threshold voltage. Increasing the spine stem resistance (RSS) or increasing the input resistance at the spinal base (RSB) also lowered the spike threshold voltage. Because a preexisting dendritic depolarization reduced the spine stem current, this lowered the spike threshold voltage, and this threshold was also shown to be sensitive to the distribution of membrane potential along the dendrite. 3. For each set of spine and dendritic parameters, there was an optimal range of RSS values for which the excitable properties at the spine head membrane resulted in maximal amplification of the dendritic excitatory postsynaptic potential (EPSP), when compared with that produced by a corresponding passive spine. This optimal range depended (with nonlinear sensitivity) on the properties of the voltage-gated channels at the spine head membrane. The maximal amplification found (for each of several sets of parameters) ranged from two to thirteen times. 4. Near this optimal range of RSS values, there was maximal (nonlinear) sensitivity of the dendritic EPSP amplitude to small changes in RSS. A minor decrease resulted in a subthreshold response at the spine head, and this resulted in a large decrease in the EPSP amplitude at the spine base. Increasing the value of RSS above this optimal range decreased the amount of spine stem current flowing to the spine base (by Ohm's law); this decreased the EPSP amplitude at the spine base. The demonstration of this optimum agrees with earlier expectations and results. 5. Excitable dendritic spines can be seen to provide an anatomical arrangement that economizes both excitable and synaptic channels. A small number of these channels (located in spine head membrane) can produce a large dendritic depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of APP for dendritic spine formation and stability

The amyloid precursor protein (APP) is transported in high amounts to the presynaptic endings where its function is still unknown. Several studies indicate that lack of APP or its overexpression affects the number of dendritic spines, the postsynaptic compartment of excitatory synapses. Since synapse loss has been identified as one of the most important structural correlates of cognitive decline in Alzheimer's diseases (AD), the physiological function of APP at synapses, specifically at dendritic spines, has come into focus in AD research. This review intends to give an overview of the very controversial results on APP expression on dendritic spine number in the mouse brain.     

Mental malfunction and memory maintenance mechanisms

Dreams appear to be generated in the process of reinforcing memory circuits of the brain, as circuits are activated by self-generated electrical slow waves, with dream contents reflecting information stored in activated circuits. Illusory dreams and other healthy delirious states appear to occur when activated memory circuits are incompetent, containing synapses whose efficacies deviate from their 'dedicated' values. Organic delirium and some other mental disorders may have their basis in brain pathologies that alter reinforcing slow waves, causing synaptic efficacies to depart from dedicated values. Activation of these incompetent circuits leads to recall of faulty memories--a substrate for delirium. In treatment of organic delirium by electroconvulsive therapy (ECT), the electric shock temporarily suppresses abnormal slow-wave regimes, allowing remedial reinforcement regimes to resume. These restore dedicated synaptic efficacies, temporarily alleviating the delirium. The action of ECT shocks appears to parallel closely that of cardiac defibrillating shocks. Greater than normal amounts of circuit reinforcement protect sensory circuitry in fatal familial insomnia, and cognitive circuitry in encephalitis lethargica.     

Activity-induced targeting of profilin and stabilization of dendritic spine morphology

Morphological changes in dendritic spines have been implicated in connective plasticity in brain circuitry, but the underlying pathway leading from synaptic transmission to structural change is unknown. Using primary neurons expressing GFP-tagged proteins, we found that profilin, a regulator of actin polymerization, is targeted to spine heads when postsynaptic NMDA receptors are activated and that actin-based changes in spine shape are concomitantly blocked. Profilin targeting was triggered by electrical stimulation patterns known to induce the long-term changes in synaptic responsiveness associated with memory formation. These results suggest that, in addition to electrophysiological changes, NMDA receptor activation initiates changes in the actin cytoskeleton of dendritic spines that stabilize synaptic structure.