Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules

It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L ₁-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum.     

大鼠初级传入纤维与脊髓背角神经元间的动作电序列的突触传递

外周感觉神经元通过动作电位序列对信号进行编码,这些动作电位序列经过突触传递最终到达脑部。但是各种脉冲序列如何通过神经元之间的化学突触进行传递依然是一个悬而未决的问题。研究了初级传入A6纤维与背角神经元之间各种动作电位序列的突触传递过程。用于刺激的规则,周期、随机脉冲序列由短簇脉冲或单个脉冲构成。定义“事件”(event)为峰峰问期(intefspike interval)小于或等于规定阈值的最长动作电位串,然后从脉冲序列中提取事件间间期(interevent interval,IEI)。用时间,IEI图与回归映射的方法分析IEI序列,结果表明在突触后输出脉冲序列中可以检测到突触前脉冲序列的主要时间结构特征,特别是在短簇脉冲作为刺激单位时。通过计算输入与输出脉冲序列的互信息,发现短簇脉冲可以更可靠地跨突触传递由输入序列携带的神经信息。这些结果表明外周输入脉冲序列的主要时间结构特征可以跨突触传递,在突触传递神经信息的过程中短簇脉冲更为有效。这一研究在从突触传递角度探索神经信息编码方面迈出了一步。     

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.     

Long-Term Culture of Astrocytes Attenuates the Readily Releasable Pool of Synaptic Vesicles

The astrocyte is a major glial cell type of the brain, and plays key roles in the formation, maturation, stabilization and elimination of synapses. Thus, changes in astrocyte condition and age can influence information processing at synapses. However, whether and how aging astrocytes affect synaptic function and maturation have not yet been thoroughly investigated. Here, we show the effects of prolonged culture on the ability of astrocytes to induce synapse formation and to modify synaptic transmission, using cultured autaptic neurons. By 9 weeks in culture, astrocytes derived from the mouse cerebral cortex demonstrated increases in β-galactosidase activity and glial fibrillary acidic protein (GFAP) expression, both of which are characteristic of aging and glial activation in vitro. Autaptic hippocampal neurons plated on these aging astrocytes showed a smaller amount of evoked release of the excitatory neurotransmitter glutamate, and a lower frequency of miniature release of glutamate, both of which were attributable to a reduction in the pool of readily releasable synaptic vesicles. Other features of synaptogenesis and synaptic transmission were retained, for example the ability to induce structural synapses, the presynaptic release probability, the fraction of functional presynaptic nerve terminals, and the ability to recruit functional AMPA and NMDA glutamate receptors to synapses. Thus the presence of aging astrocytes affects the efficiency of synaptic transmission. Given that the pool of readily releasable vesicles is also small at immature synapses, our results are consistent with astrocytic aging leading to retarded synapse maturation.     

Single vesicle tracking for studying synaptic vesicle dynamics in small central synapses

Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic vesicle dynamics in synapses remain elusive because of technical limitations. Recent advances in fluorescence imaging techniques have enabled the tracking of single synaptic vesicles in small central synapses in living neurons. Single vesicle tracking has uncovered a wealth of new information about synaptic vesicle dynamics both within and outside presynaptic terminals, showing that single vesicle tracking is an effective tool for studying synaptic vesicle dynamics. Particularly, single vesicle tracking with high spatiotemporal resolution has revealed the dependence of synaptic vesicle dynamics on the location, stages of recycling, and neuronal activity. This review summarizes the recent findings from single synaptic vesicle tracking in small central synapses and their implications in synaptic transmission and pathogenic mechanisms of neurodegenerative diseases.     

Encoding of luminance and contrast by linear and nonlinear synapses in the retina

Understanding how neural circuits transmit information is technically challenging because the neural code is contained in the activity of large numbers of neurons and synapses. Here, we use genetically encoded reporters to image synaptic transmission across a population of sensory neurons-bipolar cells in the retina of live zebrafish. We demonstrate that the luminance sensitivities of these synapses varies over 10(4) with a log-normal distribution. About half the synapses made by ON and OFF cells alter their polarity of transmission as a function of luminance to generate a triphasic tuning curve with distinct maxima and minima. These nonlinear synapses signal temporal contrast with greater sensitivity than linear ones. Triphasic tuning curves increase the dynamic range over which bipolar cells signal light and improve the efficiency with which luminance information is transmitted. The most efficient synapses signaled luminance using just 1 synaptic vesicle per second per distinguishable gray level.     

Neuroenergetics and the kinetic design of excitatory synapses

Why is the characteristic timescale of neural information processing in the millisecond range, corresponding to a 'clock speed' of about 1 kHz, whereas the clock speed of modern computers is about 3 GHz? Here we investigate how the brain's energy supply limits the maximum rate at which the brain can compute, and how the molecular components of excitatory synapses have evolved properties that are matched to the information processing they perform.     

NMDA受体参与小鼠的前额扣带回的神经突触传递

谷氨酸性突触是哺乳动物神经系统的主要兴奋性突触。在正常条件下,大多数的突触反应是由谷氨酸的AMPA受体传递的。NMDA受体在静息电位下为镁离子抑制。在被激活时,NMDA受体主要参与突触的可塑性变化。但是,许多NMDA受体拮抗剂在全身或局部注射时能产生行为效应,提示NMDA受体可能参与静息状态的生理功能。此文中,我们在离体的前额扣带回脑片上进行电生理记录,发现NMDA受体参与前额扣带回的突触传递。在重复刺激或近于生理性温度时,NMDA受体传递的反应更为明显。本文直接显示了NMDA受体参与前额扣带回的突触传递,并提示NMDA受体在前额扣带回中起着调节神经元兴奋的重要作用。     

Synaptic plasticity of NMDA receptors: mechanisms and functional implications

Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain.     

Astrocytes optimize the synaptic transmission of information

Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.     

LTP and LTD: an embarrassment of riches

LTP and LTD, the long-term potentiation and depression of excitatory synaptic transmission, are widespread phenomena expressed at possibly every excitatory synapse in the mammalian brain. It is now clear that "LTP" and "LTD" are not unitary phenomena. Their mechanisms vary depending on the synapses and circuits in which they operate. Here we review those forms of LTP and LTD for which mechanisms have been most firmly established. Examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.     

Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons

AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.     

Electrical feedback in the chemical synapses

Electrical feedback in chemical synapses and the efficacy of synaptic transmission grow with the increase in the gap resistance, so they should be higher in invaginated synapses than in the flat ones. So the plastic changes in the invagination depth may provide a morphological basis for long-term changes in synaptic efficacy: long-term potentiation (LTP) in brain and retinal synapses. In retinal photoreceptor triad synapses, the electrical feedback can provide an "operational" (instantaneous) control of synaptic transmission.     

SynPAnal: Software for Rapid Quantification of the Density and Intensity of Protein Puncta from Fluorescence Microscopy Images of Neurons

Continuous modification of the protein composition at synapses is a driving force for the plastic changes of synaptic strength, and provides the fundamental molecular mechanism of synaptic plasticity and information storage in the brain. Studying synaptic protein turnover is not only important for understanding learning and memory, but also has direct implication for understanding pathological conditions like aging, neurodegenerative diseases, and psychiatric disorders. Proteins involved in synaptic transmission and synaptic plasticity are typically concentrated at synapses of neurons and thus appear as puncta (clusters) in immunofluorescence microscopy images. Quantitative measurement of the changes in puncta density, intensity, and sizes of specific proteins provide valuable information on their function in synaptic transmission, circuit development, synaptic plasticity, and synaptopathy. Unfortunately, puncta quantification is very labor intensive and time consuming. In this article, we describe a software tool designed for the rapid semi-automatic detection and quantification of synaptic protein puncta from 2D immunofluorescence images generated by confocal laser scanning microscopy. The software, dubbed as SynPAnal (for Synaptic Puncta Analysis), streamlines data quantification for puncta density and average intensity, thereby increases data analysis throughput compared to a manual method. SynPAnal is stand-alone software written using the JAVA programming language, and thus is portable and platform-free.     

Astrocytes in endocannabinoid signalling

Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour.     

Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins

Synaptic transmission underlies every aspect of brain function. Excitatory synapses, which release the neurotransmitter glutamate, are the most numerous type of synapse in the brain. The trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to and from these synapses controls the strength of excitatory synaptic transmission. However, the underlying mechanisms controlling this trafficking have remained elusive. Recent studies, drawing from advances in molecular biology and electrophysiology techniques, have established an essential role for a family of synaptic scaffolding molecules, known as membrane associate guanylate kinases (MAGUKs), in this trafficking process. These studies highlight the remarkable orchestration of AMPA-type glutamate receptor synaptic trafficking by multiple MAGUKs at different synapses within the same neuron and at different developmental stages.     

A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation

Formation of glutamatergic synapses entails development of "silent" immature contacts into mature functional synapses. To determine how this transformation occurs, we investigated the development of neurotransmission at single synapses in vitro. Maturation of presynaptic function, assayed with endocytotic markers, followed accumulation of synapsin I. During this period, synaptic transmission was primarily mediated by activation of NMDA receptors, suggesting that most synapses were functionally silent. However, local glutamate application to silent synapses indicated that these synapses contained functional AMPA receptors, suggesting a possible presynaptic locus for silent transmission. Interference with presynaptic vesicle fusion by exposure to tetanus toxin reverted functional to silent transmission, implicating SNARE-mediated fusion as a determinant of the ratio of NMDA:AMPA receptor activation. This work reveals that functional maturation of synaptic transmission involves transformation of presynaptic silent secretion into mature synaptic transmitter release.