Beyond the connectome: how neuromodulators shape neural circuits

Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically-defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans, Drosophila, and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple circuits, some of which are active and some of which are latent at any given time.     

Spike timing precision of neuronal circuits

Spike timing is believed to be a key factor in sensory information encoding and computations performed by the neurons and neuronal circuits. However, the considerable noise and variability, arising from the inherently stochastic mechanisms that exist in the neurons and the synapses, degrade spike timing precision. Computational modeling can help decipher the mechanisms utilized by the neuronal circuits in order to regulate timing precision. In this paper, we utilize semi-analytical techniques, which were adapted from previously developed methods for electronic circuits, for the stochastic characterization of neuronal circuits. These techniques, which are orders of magnitude faster than traditional Monte Carlo type simulations, can be used to directly compute the spike timing jitter variance, power spectral densities, correlation functions, and other stochastic characterizations of neuronal circuit operation. We consider three distinct neuronal circuit motifs: Feedback inhibition, synaptic integration, and synaptic coupling. First, we show that both the spike timing precision and the energy efficiency of a spiking neuron are improved with feedback inhibition. We unveil the underlying mechanism through which this is achieved. Then, we demonstrate that a neuron can improve on the timing precision of its synaptic inputs, coming from multiple sources, via synaptic integration: The phase of the output spikes of the integrator neuron has the same variance as that of the sample average of the phases of its inputs. Finally, we reveal that weak synaptic coupling among neurons, in a fully connected network, enables them to behave like a single neuron with a larger membrane area, resulting in an improvement in the timing precision through cooperation.     

Regulation of motor circuit assembly by spatial and temporal mechanisms

Precision of synaptic connections in neuronal circuits is the product of an orderly assembly process during development. Circuits controlling motor behavior have been studied extensively in many animal species, allowing an assessment of evolutionarily conserved organizational principles that underlie neuronal subtype specification, connectivity and function. Across phylogenetically distant species, motor circuit assembly is based on spatial organization of interconnected circuit elements. Developmental molecular coordinate systems demarcate dendritic and axonal targeting territories, thereby regulating convergence of synaptic partners. Additional mechanisms subsequently control fine synaptic connection specificity within these domains. Spatial organization often correlates with the orderly sequence of neurogenesis contributing to the generation of distinct postmitotic neuronal subpopulations, a developmental strategy implemented far beyond motor circuits.     

Progress in neural plasticity

The year 2009 marks the tenth anniversary of the founding of Institute of Neuroscience (ION) in the Shanghai campus of Chinese Academy of Sciences.     

突触可塑性与脑疾病的神经发育基础

大脑神经回路高度有序的神经元活动是高级脑功能的基础,神经元之间的突触联结是神经回路的关键功能节点。神经突触根据神经元活动调整其传递效能的能力,亦即突触可塑性,被认为是神经回路发育和学习与记忆功能的基础。其异常则可能导致如抑郁症和阿尔茨海默病等精神、神经疾病。将介绍这两种疾病与突触可塑性的关系,聚焦于相关分子和细胞机制以及新的研究、治疗手段等进展。     

A trace of silence: memory and microRNA at the synapse

Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?     

Normal protein composition of synapses in Ts65Dn mice: a mouse model of Down syndrome

Down syndrome (DS) is the most prevalent form of intellectual disability caused by the triplication of ∼230 genes on chromosome 21. Recent data in Ts65Dn mice, the foremost mouse model of DS, strongly suggest that cognitive impairment in individuals with DS is a consequence of reduced synaptic plasticity because of chronic over-inhibition. It remains unclear however whether changes in plasticity are tied to global molecular changes at synapses, or are due to regional changes in the functional properties of synaptic circuits. One interesting framework for evaluating the activity state of the DS brain comes from in vitro studies showing that chronic pharmacological silencing of neuronal excitability orchestrates stereotyped changes in the protein composition of synaptic junctions. In the present study, we use proteomic strategies to evaluate whether synapses from the Ts65Dn cerebrum carry signatures characteristic of inactive cortical neurons. Our data reveal that synaptic junctions do not exhibit overt alterations in protein composition. Only modest changes in the levels of synaptic proteins and in their phosphorylation are observed. This suggests that subtle changes in the functional properties of specific synaptic circuits rather than large-scale homeostatic shifts in the expression of synaptic molecules contribute to cognitive impairment in people with DS.     

Presynaptic function

Changing the strength of synapses is key to the adaptive modifications of what neuronal circuits compute. Unsurprisingly, many different mechanisms have evolved to alter synaptic strength. Some of these mechanisms depend on the history of synaptic use, others reflect the activity of modulatory neurons that are controlled through neural computations, and still others involve more global measures of neural activity. The molecular machinery synapses use to convey information from one neuron to the next not only plays an essential part in brain function but also is at the basis of processes that are vital to all cells. Because membrane fusion events at synapses are so precisely controlled, synapses offer an especially favorable system in which to study these basic processes. Here, I review some of the recent progress that has been made in understanding both how synaptic strength is regulated and how fundamental cell biological mechanisms are used to accomplish neuronal intercommunication.     

Clique of Functional Hubs Orchestrates Population Bursts in Developmentally Regulated Neural Networks

It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity.     

Contour of auto- and cross-correlation histograms of the spike flows of monosynaptically connected neurons

By methods of neuronal interaction modelling--biomathematical (computer controlled experiment on molluscs neurones) and mathematical--in wide physiological ranges of parameters values, characterizing properties and conditions of neurones and synapses functioning, the forms were studied of auto- and cross-correlation histograms of impulse flows of neurones at forward and backward monosynaptic connections between them. Specific form is established of cross-correlation histogram of impulse flows of interconnected neurones in conditions typical of CNS of mammals, when the neurones are subjected to intensive random afferent synaptic bombardment and do not reveal any pace-maker properties. It is also shown that random afferent synaptic bombardment prevents the appearance of excitation reverberation in closed neuronal circuits.     

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity.     

Calcium signaling in neuronal development

The development of the nervous system involves the generation of a stunningly diverse array of neuronal subtypes that enable complex information processing and behavioral outputs. Deciphering how the nervous system acquires and interprets information and orchestrates behaviors will be greatly enhanced by the identification of distinct neuronal circuits and by an understanding of how these circuits are formed, changed, and/or maintained over time. Addressing these challenging questions depends in part on the ability to accurately identify and characterize the unique neuronal subtypes that comprise individual circuits. Distinguishing characteristics of neuronal subgroups include but are not limited to neurotransmitter phenotype, dendritic morphology, the identity of synaptic partners, and the expression of constellations of subgroup-specific proteins, including ion channel subtypes.     

Digitalizing neuronal synapses with cryo-electron tomography and correlative microscopy

Synapses are the structural and functional joints of neuronal circuits, and brain function is fundamentally based on synaptic quantal transmission and plasticity. Precise mapping of key components within individual synapses in different states can reveal the principles governing synapse formation, transmission, and plasticity and improving understanding of the mechanisms of synapse-related diseases. Cryo-electron tomography (cryo-ET) and correlative microscopy are increasingly powerful tools that can dissect the molecular sociology of intact cells, including neuronal synapses. In this study, we discuss current progress made in cryo-ET studies assessing neuronal synapses, especially sample preparation, molecule identification, and correlative approaches for synaptic dynamics and functions.     

A neuromime system for neural circuit analysis

A system of electronic analog neurons (neuromines) for modeling the activity in small neuronal networks is described. The system consists of sixteen analogs that simulate the integrative neuronal properties at the axon hillock and sixty-four analogs that serve to simulate synaptic interactions. The neuromime properties are based on a potential model incorporating the following properties: membrane potential, threshold, refractory period, adaption, post-inhibitory rebound, accommodation and pacemaker potential. Use of matrix switch boards provides for convenient interconnection of the neuromime elements, allowing the construction of even complex circuits.     

Brain-derived neurotrophic factor-tropomyosin-related kinase B signaling contributes to activity-dependent changes in synaptic proteins

The ability of synapses to undergo changes in structure and function in response to alterations of neuronal activity is an essential property of neural circuits. One way that this is achieved is through global changes in the molecular composition of the synapse; however, it is not clear how these changes are coupled to the dynamics of neuronal activity. Here we found that, in cultured rat cortical neurons, bidirectional changes of neuronal activity led to corresponding alterations in the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor tropomyosin-related kinase B (TrkB), as well as in the level of synaptic proteins. Exogenous BDNF reversed changes in synaptic proteins induced by chronic activity blockade, while inhibiting Trk kinase activity or depleting endogenous BDNF abolished the concentration changes induced by chronic activity elevation. Both tetrodotoxin and bicuculline had significant, but opposite, effects on synaptic protein ubiquitination in a time-dependent manner. Furthermore, exogenous BDNF was sufficient to increase ubiquitination of synaptic proteins, whereas scavenging endogenous BDNF or inhibiting Trk kinase activity prevented the ubiquitination of synaptic proteins induced by chronic elevation of neuronal activity. Inhibiting the proteasome or blocking protein polyubiquitination mimicked the effect of tetrodotoxin on the levels of synaptic proteins and canceled the effects of BDNF. Our study indicates that BDNF-TrkB signaling acts upstream of the ubiquitin proteasome system, linking neuronal activity to protein turnover at the synapse.     

Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3β cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3β activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3β activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3β can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3β neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3β, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3β activity sustains abnormal excitability in the development of epilepsy and other GSK-3β-linked human diseases.     

The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study

The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.