Secretory trafficking in neuronal dendrites

The neuronal secretory pathway represents the intracellular route for proteins involved in synaptic transmission and plasticity, as well as lipids required for outgrowth and remodelling of dendrites and axons. Although neurons use the same secretory compartments as other eukaryotic cells, the enormous distances involved, as well as the unique morphology of the neuron and its signalling requirements, challenge canonical models of secretory pathway organization. Here, we review evidence for a distributed secretory pathway in neurons, suggest mechanisms that may regulate secretory compartment distribution, and discuss the implications of a distributed secretory pathway for neuronal morphogenesis and neural-circuit plasticity.     

Self-organizing mechanism for the formation of ordered neural mappings

A model for the formation of ordered neural mappings in general, and of retinotectal connections, in particular is given. The main point came from the theory of noise induced transitions, i.e. order may be the result of the interplay between deterministic and random interactions. An activity-dependent self-organizing mechanism is presented in terms of modifiable synapses. Simulation experiments were done not only for the normal ontogenetic development but also for the plastic behaviour of the retinotopic connections.     

Spatial electrical patterns in simulated neuronal dendrites

Steady state longitudinal distributions of (a) the density of channels conducting an inward transmembrane current of cations, (b) the submembrane concentrations of these cations, and (c) the resting membrane potential, were investigated in a phenomenological model of a cylinder-shaped dendritic process of the neuron. It was found that spatially non-uniform patterns of these distributions occur only if one of the following conditions held (i) an increase in the intracellular concentration of cations conducting an inward passive transmembrane current amplified the active efflux of those cations by the pump and attenuated their passive influx through the voltage dependent channels, with amplification of the efflux lower than attenuation of the influx; (ii) molecules of mobile channels bore a negative electrophoretic charge exposed to the intracellular space and were subject to lateral electrodiffusion in the membrane; (iii) the cations induced a further release of cations from intracellular stores. Numerical simulation studies of the membrane with Na and K channels and Na/K pumps with conditions (i) and (ii) have demonstrat-ed the possibility of the creation of inhomogeneous patterns in the neurites. These inhomogeneous patterns are dissipative structures (DSs), and they can be spatially periodic. Received: 23 October 1996 / Accepted: 21 May 1997     

Septin 6 localizes to microtubules in neuronal dendrites

In neuronal dendrites, septins localize to the base of the spine, a unique position which is sandwiched between the microtubule (MT)-rich dendritic shaft and the actin filament-rich spine. Here, we provide evidence for the association of SEPT6 with MTs in cultured rat hippocampal neurons. In normal cultures, SEPT6 clusters localized to MTs, but not to actin clusters. Only MT-disrupting agents (vincristine and nocodazole), but not microfilament-disrupting one (latrunculin A), induced the redistribution of SEPT6 to the disrupted MTs. The nascent MT fibers that were recovered from vincristine or nocodazole treatments also accompanied SEPT6. Blocking MT disruption by Taxol prevented such phenomena, proving that the redistribution of SEPT6 was due to the MT disruption. Our results indicate that SEPT6 complexes at the base of the dendritic spine are associated with MTs.     

Comparison of active transport in neuronal axons and dendrites

This paper presents a theoretical study, based on modified Smith-Simmons equations, that compares transport of intracellular organelles in two different neurite outgrowths, dendrites and axons. It is demonstrated that the difference in microtubule polarity orientations in dendrites and axons has significant implications on motor-assisted transport in these neurite outgrowths. The developed approach presents a qualitative theoretical basis for understanding important questions such as why axons exhibit almost an unlimited grows potential in vitro while dendrites remain relatively short. It is shown that the difference in a microtubule polarity arrangement between axons and dendrites may be a regulatory mechanism for limiting dendritic growth. Other biological implications of the developed theory as well as other possible reasons for the difference in microtubule structure between axons and dendrites are discussed.     

Transfer properties of neuronal dendrites with tonically activated conductances

The somatopetal current transfer was studied in the mathematical models of a reconstructed brainstem motoneuron with tonically activated excitatory synaptic inputs uniformly distributed over dendritic arborization. The soma and axon provided a constant passive leak. The extrasynaptic dendritic membrane was either passive or active (of a Hodgkin-Huxley type). The longitudinal membrane current density (per unit path length) was used as an estimate of the current transfer effectiveness of different dendritic paths. Introduction of a steady uniform voltage-independent conductance per unit membrane area simulated such a synaptic activation. This actions always produced a spatially inhomogeneous membrane depolarization decaying from the distal dendritic tips toward the soma. The reason for such an inhomogeneity was the preponderance of somatopetal over somatofugal input conductance at every site in the dendrites with sealed distal ends and a leaky somatic end. In active dendrites, partial voltage-dependent extrasynaptic conductances followed this depolarization according to their activation-inactivation kinetics. The greater the local depolarization, the greater the contribution of the non-inactivating potassium conductance to the total membrane conductance. The contribution of the inactivated sodium conductance was one order of magnitude smaller. Correspondingly, the effective equilibrium potential of the total transmembrane current became spatially inhomogeneous and shifted to the potassium equilibrium potential. In the passive dendrites, the equilibrium potential remained spatially homogeneous. Inhomogeneities of the dendritic geometry (abrupt change in the diameter and, especially, asymmetrical branching) caused characteristic perturbations in the voltage gradient, so that the path profiles of the voltage, conductances, and currents diverged. This indicated a geometry-induced separation of the dendritic paths in their transfer effectiveness. Active dendrites of the same geometry were less effective than passive ones due to the effect of the potassium conductance associated with the hyperpolarizing equilibrium potential.     

Self-organizing circuit assembly through spatiotemporally coordinated neuronal migration within geometric constraints

Background

Neurons are dynamically coupled with each other through neurite-mediated adhesion during development. Understanding the collective behavior of neurons in circuits is important for understanding neural development. While a number of genetic and activity-dependent factors regulating neuronal migration have been discovered on single cell level, systematic study of collective neuronal migration has been lacking. Various biological systems are shown to be self-organized, and it is not known if neural circuit assembly is self-organized. Besides, many of the molecular factors take effect through spatial patterns, and coupled biological systems exhibit emergent property in response to geometric constraints. How geometric constraints of the patterns regulate neuronal migration and circuit assembly of neurons within the patterns remains unexplored.

Methodology/Principal Findings

We established a two-dimensional model for studying collective neuronal migration of a circuit, with hippocampal neurons from embryonic rats on Matrigel-coated self-assembled monolayers (SAMs). When the neural circuit is subject to geometric constraints of a critical scale, we found that the collective behavior of neuronal migration is spatiotemporally coordinated. Neuronal somata that are evenly distributed upon adhesion tend to aggregate at the geometric center of the circuit, forming mono-clusters. Clustering formation is geometry-dependent, within a critical scale from 200 µm to approximately 500 µm. Finally, somata clustering is neuron-type specific, and glutamatergic and GABAergic neurons tend to aggregate homo-philically.

Conclusions/Significance

We demonstrate self-organization of neural circuits in response to geometric constraints through spatiotemporally coordinated neuronal migration, possibly via mechanical coupling. We found that such collective neuronal migration leads to somata clustering, and mono-cluster appears when the geometric constraints fall within a critical scale. The discovery of geometry-dependent collective neuronal migration and the formation of somata clustering in vitro shed light on neural development in vivo.     

Changes in the cortical neuronal dendrites in experimental alcoholic intoxication

The state of the cortical neuron dendrites was studied in rats at various stages of alcohol intoxication; two categories of changes occurred in dendrites--destructive and compensatory. These changes depended on the stages of alcohol intoxication and individual peculiarities of the central nervous system of the animals.     

Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites

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Highlights? The endoplasmic reticulum (ER) in dendrites shows spatial variation in complexity ? Increased complexity occurs at dendritic branch points, confining membrane cargo ? An mGluR/PKC/CLIMP63 pathway bidirectionally regulates ER complexity ? ER complexity controls dendritic morphogenesis and defines sites of branch formation     

Messenger RNAs in dendrites: localization,stability, and implications for neuronal function

In the mammalian central nervous system (CNS), each neuron receives signals from other neurons through numerous synapses located on its cell body and dendrites. Molecules involved in the postsynaptic signaling pathways need to be targeted to the appropriate subcellular domains at the right time during both synaptogenesis and the maintenance of synaptic functions. The presence of messenger RNAs (mRNAs) in dendrites offers a mechanism for synthesizing the appropriate molecules at the right place in response to local extracellular stimuli. Several dendritic mRNAs have been identified, and the mechanisms controlling their localization are beginning to be understood. In many cell types, controls on mRNA stability play an important role in the regulation of gene expression, but it is unclear to what extent this type of control operates in dendrites. The regulation of protein synthesis and the control of mRNA stability in dendrites could have important implications for neuronal function. BioEssays 20:70–78, 1998. © 1998 John Wiley & Sons, Inc.     

HGF regulates the development of cortical pyramidal dendrites

Although hepatocyte growth factor (HGF) and its receptor tyrosine kinase MET are widely expressed in the developing and mature central nervous system, little is known about the role of MET signaling in the brain. We have used particle-mediated gene transfer in cortical organotypic slice cultures established from early postnatal mice to study the effects of HGF on the development of dendritic arbors of pyramidal neurons. Compared with untreated control cultures, exogenous HGF promoted a highly significant increase in dendritic growth and branching of layer 2 pyramidal neurons, whereas inactivation of endogenous HGF with function-blocking, anti-HGF antibody caused a marked reduction in size and complexity of the dendritic arbors of these neurons. Furthermore, pyramidal neurons transfected with an MET dominant-negative mutant receptor likewise had much smaller and less complex dendritic arbors than did control transfected neurons. Our results indicate that HGF plays a role in regulating dendritic morphology in the developing cerebral cortex.     

Geometry-induced features of current transfer in neuronal dendrites with tonically activated conductances

The impact of dendritic geometry on somatopetal transfer of the current generated by steady uniform activation of excitatory synaptic conductance distributed over passive, or active (Hodgkin-Huxley type), dendrites was studied in simulated neurons. Such tonic activation was delivered to the uniform dendrite and to the dendrites with symmetric or asymmetric branching with various ratios of branch diameters. Transfer effectiveness of the dendrites with distributed sources was estimated by the core current increment directly related to the total membrane current per unit path length. The effectiveness decreased with increasing path distance from the soma along uniform branches. The primary reason for this was the asymmetry of somatopetal vs somatofugal input core conductance met by synaptic current due to a greater leak conductance at the proximal end of the dendrite. Under these conditions, an increasing somatopetal core current and a corresponding drop of the depolarization membrane potential occurred. The voltage-dependent extrasynaptic conductances, if present, followed this depolarization. Consequently, the driving potential and membrane current densities decreased with increasing path distance from the soma. All path profiles were perturbed at bifurcations, being identical in symmetrical branches and diverging in asymmetrical ones. These perturbations were caused by voltage gradient breaks (abrupt change in the profile slope) occurring at the branching node due to coincident inhomogeneity of the dendritic core cross-section area and its conductance. The gradient was greater on the side of the smaller effective cross-section. Correspondingly, the path profiles of the somatopetal current transfer effectiveness were broken and/or diverged. The dendrites, their paths, and sites which were more effective in the current transfer from distributed sources were also more effective in the transfer from single-site inputs. The effectiveness of the active dendrite depended on the activation-inactivation kinetics of its voltage-gated conductances. In particular, dendrites with the same geometry were less effective with the Hodgkin-Huxley membrane than with the passive membrane, because of the effect of the noninactivating K⁺-conductance associated with the hyperpolarization equilibrium potential. Such electrogeometrical coupling may form a basis for path-dependent input-output conversion in the dendritic neurons, as the output discharge rate is defined by the net current delivered to the soma. Received: 18 December 1997 / Accepted in revised form: 12 June 1998     

神经元极化的分子机制

神经元发育过程中轴突和树突的分化和形成是神经元极化建立的标志,也是建立神经信号转导的基础.近年来,神经元极化的分子机制有了重大突破,发现神经元细胞骨架微丝和微管的结构和功能的改变最终调节着极化的建立.其中,细胞内信号转导途径以及一些激酶参与了调节细胞骨架微丝和微管的结构和功能,最终使神经元极化建立.     

Neural development: axon regeneration derailed by dendrites

Maturing neurons gradually lose the ability to regenerate axons. In the retina, signals from neighboring cells have been found to induce a perinatal switch from extension of axons to extension of dendrites, a change that may contribute to regeneration failure.     

Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits

Developing neurons can change axonal and dendritic fate upon axonal lesion, but it is unclear whether neurons retain such plasticity when they are synaptically interconnected. To address whether polarity is reversible in mature neurons, we cut the axon of GFP-labeled hippocampal neurons in dissociated and organotypic cultures and found that a new axon arose from a mature dendrite. The regenerative response correlated with the length of the remaining stump: proximal axotomies (<35 microm) led to the transformation of a dendrite into an axon (identity change), whereas distal cuts (>35 microm) induced axon regrowth, similar to what is seen in young neurons. Searching for a putative landmark in the distal axon that could determine axon identity, we focused on the stability of microtubules, which regulate initial neuronal polarization during early development. We found that functionally polarized neurons contain a distinctively high proportion of stable microtubules in the distal axon. Moreover, pharmacological stabilization of microtubules was sufficient to induce the formation of multiple axons out of differentiated dendrites. Our data argue that mature neurons integrated in functional networks remain flexible in their polarity and that mechanisms acting during initial axon selection can be reactivated to induce axon growth out of functionally mature dendrites.     

Ion concentration dynamics as a mechanism for neuronal bursting

We describe a simple conductance-based model neuron that includes intra- and extracellular ion concentration dynamics and show that this model exhibits periodic bursting. The bursting arises as the fast-spiking behavior of the neuron is modulated by the slow oscillatory behavior in the ion concentration variables and vice versa. By separating these time scales and studying the bifurcation structure of the neuron, we catalog several qualitatively different bursting profiles that are strikingly similar to those seen in experimental preparations. Our work suggests that ion concentration dynamics may play an important role in modulating neuronal excitability in real biological systems.     

Caspases and neuronal development

Recent developments have shown that inappropriate activation of apoptotic pathways contributes to many neurodegenerative diseases. The basic mechanisms that underlie apoptosis in neurodegenerative diseases are uncertain, although they likely represent the subversion of normal developmental programs. Several types of neuronal cell death have been reported, including autophagic and caspase-independent cell death. In this review we consider evidence for the participation of apoptotic caspases in neuronal development, and examine the hypothesis that differentiating neurons undergo stage-specific alterations in apoptosis sensitivity that may be due to caspase regulation. In addition, we present data supporting this hypothesis.     

Spatial heterogeneity of passive electrical transfer properties of neuronal dendrites due to their metrical asymmetry

The complex and diverse geometry of neuronal dendrites determines the different morphological types of neurons and influences the generation of complex and diverse discharge patterns at the cell output. The recent finding that each temporal pattern has its spatial signature in the form of a combination of high- and low-depolarization states of asymmetrical dendritic branches with active membrane properties raises the question of the nature of such characteristic spatial heterogeneity of electrical states. To answer this, we consider passive dendrites as a conventional reference case using the known current transfer functions, which we complete by corresponding parametric sensitivity functions. These functions for metrically asymmetrical bifurcations of different sizes, as the simplest elements constituting arborizations of arbitrary geometry, are analyzed under different membrane conductivity conditions related to the intensity of activation of ion channels. Characteristic relationships are obtained on the one hand among the size (branch lengths), metrical asymmetry (difference between sister branches in length and/or diameter), and membrane conductivity, and on the other hand, for the difference between the branches in their current transfer effectiveness as an indicator of their electrical asymmetry (heterogeneity). These relationships (i) allow the introduction of a biophysically based criterion for the electrical distinction between metrically asymmetrical branches, (ii) show how the difference first increases and then decreases with increasing membrane conductivity, and (iii) show that the greatest electrical heterogeneity occurs in a lower or higher range of conductivity, corresponding to larger or smaller bifurcation size. As a consequence, the characteristic low-, medium-, and high-conductance states are derived such that metrically asymmetrical parts of simple and complex trees are electrically distinct when the membrane conductivity lies in the size-related medium range, and indistinct otherwise.