Subplate neurons regulate maturation of cortical inhibition and outcome of ocular dominance plasticity

Synaptic plasticity during critical periods of development requires intact inhibitory circuitry. We report that subplate neurons are needed both for maturation of inhibition and for the proper sign of ocular dominance (OD) plasticity. Removal of subplate neurons prevents the developmental upregulation of genes involved in mature, fast GABAergic transmission in cortical layer 4, including GABA receptor subunits and KCC2, and thus prevents the switch to a hyperpolarizing effect of GABA. To understand the implications of these changes, a realistic circuit model was formulated. Simulations predicted that without subplate neurons, monocular deprivation (MD) paradoxically favors LGN axons representing the deprived (less active) eye, exactly what was then observed experimentally. Simulations also account for published results showing that OD plasticity requires mature inhibition. Thus, subplate neurons regulate molecular machinery required to establish an adult balance of excitation and inhibition in layer 4, and thereby influence the outcome of OD plasticity.     

Experience-dependent plasticity in adult visual cortex

Experience-dependent plasticity is a prominent feature of the mammalian visual cortex. Although such neural changes are most evident during development, adult cortical circuits can be modified by a variety of manipulations, such as perceptual learning and visual deprivation. Elucidating the underlying mechanisms at the cellular and synaptic levels is an essential step in understanding neural plasticity in the mature animal. Although developmental and adult plasticity share many common features, notable differences may be attributed to developmental cortical changes at multiple levels. These range from shifts in the molecular profiles of cortical neurons to changes in the spatiotemporal dynamics of network activity. In this review, we will discuss recent progress and remaining challenges in understanding adult visual plasticity, focusing on the primary visual cortex.     

Bidirectional activity-dependent morphological plasticity in hippocampal neurons

Dendritic spines on pyramidal neurons receive the vast majority of excitatory input and are considered electrobiochemical processing units, integrating and compartmentalizing synaptic input. Following synaptic plasticity, spines can undergo morphological plasticity, which possibly forms the structural basis for long-term changes in neuronal circuitry. Here, we demonstrate that spines on CA1 pyramidal neurons from organotypic slice cultures show bidirectional activity-dependent morphological plasticity. Using two-photon time-lapse microscopy, we observed that low-frequency stimulation induced NMDA receptor-dependent spine retractions, whereas theta burst stimulation led to the formation of new spines. Moreover, without stimulation the number of spine retractions was on the same order of magnitude as the stimulus-induced spine gain or loss. Finally, we found that the ability of neurons to eliminate spines in an activity-dependent manner decreased with developmental age. Taken together, our data show that hippocampal neurons can undergo bidirectional morphological plasticity; spines are formed and eliminated in an activity-dependent way.     

Failed Stabilization for Long-Term Potentiation in the Auditory Cortex of Fmr1 Knockout Mice

Fragile X syndrome is a developmental disorder that affects sensory systems. A null mutation of the Fragile X Mental Retardation protein 1 (Fmr1) gene in mice has varied effects on developmental plasticity in different sensory systems, including normal barrel cortical plasticity, altered ocular dominance plasticity and grossly impaired auditory frequency map plasticity. The mutation also has different effects on long-term synaptic plasticity in somatosensory and visual cortical neurons, providing insights on how it may differentially affect the sensory systems. Here we present evidence that long-term potentiation (LTP) is impaired in the developing auditory cortex of the Fmr1 knockout (KO) mice. This impairment of synaptic plasticity is consistent with impaired frequency map plasticity in the Fmr1 KO mouse. Together, these results suggest a potential role of LTP in sensory map plasticity during early sensory development.     

Mitochondrial Regulation of Neuronal Plasticity

The structure and function of neurons is dynamic during development and in adaptive responses of the adult nervous system to environmental demands. The mechanisms that regulate neuronal plasticity are poorly understood, but are believed to involve neurotransmitter and neurotrophic factor signaling pathways. In the present article, I review emerging evidence that mitochondria play important roles in regulating developmental and adult neuroplasticity. In neurons, mitochondria are located in axons, dendrites, growth cones and pre- and post-synaptic terminals where their movements and functions are regulated by local signals such as neurotrophic factors and calcium influx. Mitochondria play important roles in fundamental developmental processes including the establishment of axonal polarity and the regulation of neurite outgrowth, and are also involved in synaptic plasticity in the mature nervous system. Abnormalities in mitochondria are associated with neurodegenerative and psychiatric disorders, suggesting a therapeutic potential for approaches that target mitochondrial mechanisms. Special issue dedicated to John P. Blass.     

A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome

The function of local protein synthesis in synaptic plasticity and its dysregulation in fragile X syndrome (FXS) is well studied, however the contribution of regulated mRNA transport to this function remains unclear. We report a function for the fragile X mental retardation protein (FMRP) in the rapid, activity-regulated transport of mRNAs important for synaptogenesis and plasticity. mRNAs were deficient in glutamatergic signaling-induced dendritic localization in neurons from Fmr1 KO mice, and single mRNA particle dynamics in live neurons revealed diminished kinesis. Motor-dependent translocation of FMRP and cognate mRNAs involved the C terminus of FMRP and kinesin light chain, and KO brain showed reduced kinesin-associated mRNAs. Acute suppression of FMRP and target mRNA transport in WT neurons resulted in altered filopodia-spine morphology that mimicked the FXS phenotype. These findings highlight a mechanism for stimulus-induced dendritic mRNA transport and link its impairment in a mouse model of FXS to altered developmental morphologic plasticity.     

Spine Formation Pattern of Adult-Born Neurons Is Differentially Modulated by the Induction Timing and Location of Hippocampal Plasticity

In the adult hippocampus dentate gyrus (DG), newly born neurons are functionally integrated into existing circuits and play important roles in hippocampus-dependent memory. However, it remains unclear how neural plasticity regulates the integration pattern of new neurons into preexisting circuits. Because dendritic spines are major postsynaptic sites for excitatory inputs, spines of new neurons were visualized by retrovirus-mediated labeling to evaluate integration. Long-term potentiation (LTP) was induced at 12, 16, or 21 days postinfection (dpi), at which time new neurons have no, few, or many spines, respectively. The spine expression patterns were investigated at one or two weeks after LTP induction. Induction at 12 dpi increased later spinogenesis, although the new neurons at 12 dpi didn’t respond to the stimulus for LTP induction. Induction at 21 dpi transiently mediated spine enlargement. Surprisingly, LTP induction at 16 dpi reduced the spine density of new neurons. All LTP-mediated changes specifically appeared within the LTP–induced layer. Therefore, neural plasticity differentially regulates the integration of new neurons into the activated circuit, dependent on their developmental stage. Consequently, new neurons at different developmental stages may play distinct roles in processing the acquired information by modulating the connectivity of activated circuits via their integration.     

Rules of engagement: factors that regulate activity-dependent synaptic plasticity during neural network development

Overproduction and pruning during development is a phenomenon that can be observed in the number of organisms in a population, the number of cells in many tissue types, and even the number of synapses on individual neurons. The sculpting of synaptic connections in the brain of a developing organism is guided by its personal experience, which on a neural level translates to specific patterns of activity. Activity-dependent plasticity at glutamatergic synapses is an integral part of neuronal network formation and maturation in developing vertebrate and invertebrate brains. As development of the rodent forebrain transitions away from an over-proliferative state, synaptic plasticity undergoes modification. Late developmental changes in synaptic plasticity signal the establishment of a more stable network and relate to pronounced perceptual and cognitive abilities. In large part, activation of glutamate-sensitive N-methyl-d-aspartate (NMDA) receptors regulates synaptic stabilization during development and is a necessary step in memory formation processes that occur in the forebrain. A developmental change in the subunits that compose NMDA receptors coincides with developmental modifications in synaptic plasticity and cognition, and thus much research in this area focuses on NMDA receptor composition. We propose that there are additional, equally important developmental processes that influence synaptic plasticity, including mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor activation. The goal of this review is to summarize what is known and what is not well understood about developmental changes in functional plasticity at glutamatergic synapses, and in the end, attempt to relate these changes to maturation of neural networks.     

High frequency of ciliated neuropeptide Y-immunoreactive neurons in rat striatum

Summary An analysis of the ultrastructure of neuropeptide Y-immunoreactive neurons in rat striatum revealed the presence of a cilium in half of the neurons serially sectioned in part, and in a quarter of the neurons observed in single sections. It is speculated that the cilium is a developmental remnant, i.e., a sign of the less differentiated state of the NPY-containing neurons compared with the other neurons, and that this could explain the plasticity of this type of neuron after lesions.This work is part of the thesis of G. Wolfrum submitted to the Ludwig-Maximilians-Universität in partial fulfillment for the requirements of a Dr. rer. nat. degree     

Cadherins as regulators of neuronal polarity

A compelling amount of data is accumulating about the polyphonic role of neuronal cadherins during brain development throughout all developmental stages, starting from the involvement of cadherins in the organization of neurulation up to synapse development and plasticity. Recent work has confirmed that specifically N-cadherins play an important role in asymmetrical cellular processes in developing neurons that are at the basis of polarity. In this review we will summarize recent data, which demonstrate how N-cadherin orchestrates distinct processes of polarity establishment in neurons.     

In Vivo Imaging of Dauer-specific Neuronal Remodeling in C. elegans

The mechanisms controlling stress-induced phenotypic plasticity in animals are frequently complex and difficult to study in vivo. A classic example of stress-induced plasticity is the dauer stage of C. elegans. Dauers are an alternative developmental larval stage formed under conditions of low concentrations of bacterial food and high concentrations of a dauer pheromone. Dauers display extensive developmental and behavioral plasticity. For example, a set of four inner-labial quadrant (IL2Q) neurons undergo extensive reversible remodeling during dauer formation. Utilizing the well-known environmental pathways regulating dauer entry, a previously established method for the production of crude dauer pheromone from large-scale liquid nematode cultures is demonstrated. With this method, a concentration of 50,000 - 75,000 nematodes/ml of liquid culture is sufficient to produce a highly potent crude dauer pheromone. The crude pheromone potency is determined by a dose-response bioassay. Finally, the methods used for in vivo time-lapse imaging of the IL2Qs during dauer formation are described.     

Cadherins as regulators of neuronal polarity

A compelling amount of data is accumulating about the polyphonic role of neuronal cadherins during brain development throughout all developmental stages, starting from the involvement of cadherins in the organization of neurulation up to synapse development and plasticity. Recent work has confirmed that specifically N-cadherins play an important role in asymmetrical cellular processes in developing neurons that are at the basis of polarity. In this review we will summarize recent data, which demonstrate how N-cadherin orchestrates distinct processes of polarity establishment in neurons.     

Stem cell dogmas in the genomics era

Recently, much excitement has been generated by strong suggestions that stem cells isolated from diverse somatic tissues may have a previously unsuspected degree of developmental or differentiation plasticity. For example, a hematopoietic stem cell may be capable of producing mature liver cells, muscle tissue or even neurons. Similarly, central nervous system stem cells or muscle stem cells may be capable of producing mature blood cell populations. These observations have called into question several fundamental dogmas of developmental biology. In addition, these observations offer extraordinary promise in the clinical setting. It is of paramount importance to rigorously assess the suggested plasticity phenomena using precise clonal analysis. In order to explore the plasticity phenomena in more direct ways, it is necessary to develop in vitro systems where such behavior can be recapitulated in a well-defined setting. Finally, stem cell plasticity will be governed, at least in part, by cell-autonomous mechanisms: that is, those mediated by the panel of gene products expressed in stem cells. Therefore, it is necessary to identify the complete gene expression profile that defines the stem cell.     

大鼠生后发育过程中听皮层神经元特征频率的可塑性

应用常规电生理学技术,以神经元的特征频率和频率调谐曲线为指标,分别在生后2、3、4、5、6和8周龄SD大鼠上,研究生后发育过程中,听皮层神经元特征频率的可塑性.结果表明,在给予条件刺激频率和神经元特征频率相差1.0kHz范围内,条件刺激都可诱导各年龄组神经元特征频率向频率调谐曲线的低频端、高频端或调谐曲线的两端相应的偏移.特征频率偏移的概率与年龄相关.随着年龄的增长,特征频率偏移的比例下降,而不偏移的比例则上升.随着年龄增长,那些Q10-dB值大和频率调谐曲线对称指数大于零的神经元,特征频率偏移到频率调谐曲线高频端的比例增加更为明显(P<0.01).诱导特征频率完全偏移的时程和特征频率恢复的时程也与动物的年龄相关,随着年龄增长,诱导和恢复时程都明显延长(P<0.05).结果提示,大鼠听皮层神经元特征频率的可塑性与生后年龄相关,为深入研究中枢神经元功能活动可塑性的机制提供了重要实验资料.     

Long-term effects of the perinatal environment on respiratory control.

The respiratory control system exhibits considerable plasticity, similar to other regions of the nervous system. Plasticity is a persistent change in system behavior triggered by experiences such as changes in neural activity, hypoxia, and/or disease/injury. Although plasticity is observed in animals of all ages, some forms of plasticity appear to be unique to development (i.e., "developmental plasticity"). Developmental plasticity is an alteration in respiratory control induced by experiences during "critical" developmental periods; similar experiences outside the critical period will have little or no lasting effect. Thus complementary experiments on both mature and developing animals are generally needed to verify that the observed plasticity is unique to development. Frequently studied models of developmental plasticity in respiratory control include developmental manipulations of respiratory gas concentrations (O(2) and CO(2)). Environmental factors not specifically associated with breathing may also trigger developmental plasticity, however, including psychological stress or chemicals associated with maternal habits (e.g., nicotine, cocaine). Despite rapid advances in describing models of developmental plasticity in breathing, our understanding of fundamental mechanisms giving rise to such plasticity is poor; mechanistic studies of developmental plasticity are of considerable importance. Developmental plasticity may enable organisms to "fine tune" their phenotype to optimize the performance of this critical homeostatic regulatory system. On the other hand, developmental plasticity could also increase the risk of disease later in life. Future directions for studies concerning the mechanisms and functional implications of developmental plasticity in respiratory motor control are discussed.     

Receptors of glutamate and neurotrophin in vestibular neuronal functions

The last decade has witnessed advances in understanding the roles of receptors of neurotrophin and glutamate in the vestibular system. In the first section of this review, the biological actions of neurotrophins and their receptors in the peripheral and central vestibular systems are summarized. Emphasis will be placed on the roles of neurotrophins in developmental plasticity and in the maintenance of vestibular function in the adult animal. This is reviewed in relation to the developmental expression pattern of neurotrophins and their receptors within the vestibular nuclei. The second part is focused on the functional role of different glutamate receptors on central vestibular neurons. The developmental expression pattern of glutamate receptor subunits within the vestibular nuclei is reviewed in relation to the potential role of glutamate receptors in regulating the development of vestibular function.     

Influence of the environment on adult CNS plasticity and repair

During developmental critical periods, external stimuli are crucial for information processing, acquisition of new functions or functional recovery after CNS damage. These phenomena depend on the capability of neurons to modify their functional properties and/or their connections, generally defined as "plasticity". Although plasticity decreases after the closure of critical periods, the adult CNS retains significant capabilities for structural remodelling and functional adaptation. At the molecular level, structural modifications of neural circuits depend on the balance between intrinsic growth properties of the involved neurons and growth-regulatory cues of the extracellular milieu. Interestingly, experience acts on this balance, so as to create permissive conditions for neuritic remodelling. Here, we present an overview of recent findings concerning the effects of experience on cellular and molecular processes responsible for producing structural plasticity of neural networks or functional recovery after an insult to the adult CNS (e.g. traumatic injury, ischemia or neurodegenerative disease). Understanding experience-dependent mechanisms is crucial for the development of tailored rehabilitative strategies, which can be exploited alone or in combination with specific therapeutic interventions to improve neural repair after damage.     

糖皮质激素在神经系统发育中的作用

在神经系统的早期发育阶段,糖 皮质激素可通过影响下丘脑－垂体－肾上腺（ＨＰＡ）轴的活动,并经由糖 皮质激素受体介导对神经元和神经胶质的存活、分化、生长和凋亡过程进行调节;在成年阶段,糖皮质激素对与神经元可塑性相关的因子进行调节,从而影响神经元的可塑性变化;在老年阶段,过量的糖皮质激素对神经元更多地产生危害作用。因此,糖皮质激素对神经元的发育起着重要的调节作用。     

3.6 kb genomic sequence from Takifugu capable of promoting axon growth-associated gene expression in developing and regenerating zebrafish neurons

Unlike mammals, fish have the capacity for functional adult CNS regeneration, which is due, in part, to their ability to express axon growth-related genes in response to nerve injury. One such axon growth-associated gene is gap43, which is expressed during periods of developmental and regenerative axon growth, but is not expressed in CNS neurons that do not regenerate in adult mammals. We previously demonstrated that cis-regulatory elements of gap43 that are sufficient for developmental expression are not sufficient for regenerative expression in the zebrafish. Here we have identified a 3.6kb genomic sequence from Fugu rubripes that can promote reporter gene expression in the nervous system during both development and regeneration in zebrafish. This compact sequence is advantageous for functional dissection of regions important for axon growth-associated gene expression during development and/or regeneration. In addition, this sequence will also be useful for targeting gene expression to neurons during periods of growth and plasticity.