The Role of Proteases in Hippocampal Synaptic Plasticity: Putting Together Small Pieces of a Complex Puzzle

Long-term synaptic plasticity in the hippocampus is thought to underlie the formation of certain forms of memory, including spatial memory. The early phase of long-term synaptic potentiation and synaptic depression depends on post-translational modifications of synaptic proteins, while protein synthesis is also required for the late-phase of both forms of synaptic plasticity (L-LTP and L-LTD). Numerous pieces of evidence show a role for different types of proteases in synaptic plasticity, further increasing the diversity of mechanisms involved in the regulation of the intracellular and extracellular protein content. The cleavage of extracellular proteins is coupled to changes in postsynaptic intracellular mechanisms, and additional alterations in this compartment result from the protease-mediated targeting of intracellular proteins. Both mechanisms contribute to initiate signaling cascades that drive downstream pathways coupled to synaptic plasticity. In this review we summarize the evidence pointing to a role for extracellular and intracellular proteases, with distinct specificities, in synaptic plasticity. Where in the cells the proteases are located, and how they are regulated is also discussed. The combined actions of proteases and translation mechanisms contribute to a tight control of the synaptic proteome relevant for long-term synaptic potentiation and synaptic depression in the hippocampus. Additional studies are required to elucidate the mechanisms whereby these changes in the synaptic proteome are related with plasticity phenomena.     

Network Self-Organization Explains the Statistics and Dynamics of Synaptic Connection Strengths in Cortex

The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits.     

Homeostatic changes of short-term plasticity of gabaergic synaptic transmission in rat hippocampal cell cultures

It is well documented that prolonged alteration of activity in neuronal networks initiates a number of homeostatic mechanisms including compensatory changes of excitatory and inhibitory synaptic strength. We studied whether this also evokes compensatory changes of short-term synaptic transmission. Using patch-clamp technique in hippocampal cell cultures we examined the effects: of prolonged decrease of neuronal firing evoked by sodium channel blocker: tetrodotoxin (TTX) and ionotropic glutamate receptor antagonist - kynurenate; prolonged enhancement ofneuronal firing evoked by antagonist GABAA receptors - bicuculline on short-term depression of GABAergic synaptic transmission evoked by train of stimuli (5 Hz). We found that both TTX and kynurenate treatments enhance depression of GABAergic transmission, while bicuculline treatment does not. We conclude that alteration of depression of GABAergic transmission evoked by the prolonged decrease of neuronal activity may contribute to homeostatic plasticity in hippocampal neuronal networks.     

Geometry and structural plasticity of synaptic connectivity

Changes in synaptic connectivity patterns through the formation and elimination of dendritic spines may contribute to structural plasticity in the brain. We characterize this contribution quantitatively by estimating the number of different synaptic connectivity patterns attainable without major arbor remodeling. This number depends on the ratio of the synapses on a dendrite to the axons that pass within a spine length of that dendrite. We call this ratio the filling fraction and calculate it from geometrical analysis and anatomical data. The filling fraction is 0.26 in mouse neocortex, 0.22-0.34 in rat hippocampus. In the macaque visual cortex, the filling fraction increases by a factor of 1.6-1.8 from area V1 to areas V2, V4, and 7a. Since the filling fraction is much smaller than 1, spine remodeling can make a large contribution to structural plasticity.     

Impact of High-Fat Diet and Early Stress on Depressive-Like Behavior and Hippocampal Plasticity in Adult Male Rats

During development, the brain goes through fundamental processes, including organization of neural networks and plasticity. Environmental interventions may change initial brain programming, leading to long-lasting effects and altering the susceptibility to psychopathologies, including depression disorder. It is known that depression is a psychiatric disorder with a high prevalence worldwide, including high rates among adolescents. In this study, we evaluated whether social isolation in the prepubertal period and chronic use of high-fat diet (HFD) may induce depressive-like behavior in male adult rats. We also investigated hippocampal plasticity markers and neurotransmitter systems. We found both social isolation and HFD induced a depressive-like behavior in the forced swimming task. Moreover, chronic HFD reduced synaptic markers in hippocampus, demonstrated by reductions in βIII-tubulin (neuronal marker), PSD-95, SNAP-25, and neurotrophin-3. The HFD group also presented decreased glutamatergic and GABAergic receptors subunits. On the other hand, stress affected hippocampal brain-derived neurotrophic factor (BDNF) signaling pathways, and increased expression of subunit of the NMDA receptor (NR2A). Both factors (stress and diet) decreased GR in the hippocampus without affecting plasma corticosterone at basal levels. Interactions between early stress and HFD access were observed only in the BNDF receptor (tropomyosin receptor kinase B; TrkB) and synaptophysin. In summary, these findings showed that a brief social isolation and chronic HFD, during a sensitive developmental period, cause depressive-like behavior in adulthood. The mechanisms underlying these behavioral effects may involve changes in the levels of synaptic proteins in hippocampus: HFD consumption appears to affect synaptic markers, while social isolation affected BDNF signaling more significantly.     

Pattern Association and Consolidation Emerges from Connectivity Properties between Cortex and Hippocampus

The basic structure of the cortico-hippocampal system is highly conserved across mammalian species. Comparatively few hippocampal neurons can represent and address a multitude of cortical patterns, establish associations between cortical patterns and consolidate these associations in the cortex. In this study, we investigate how elementary anatomical properties in the cortex-hippocampus loop along with synaptic plasticity contribute to these functions. Specifically, we focus on the high degree of connectivity between cortex and hippocampus leading to converging and diverging forward and backward projections and heterogenous synaptic transmission delays that result from the detached location of the hippocampus and its multiple loops. We found that in a model incorporating these concepts, each cortical pattern can evoke a unique spatio-temporal spiking pattern in hippocampal neurons. This hippocampal response facilitates a reliable disambiguation of learned associations and a bridging of a time interval larger than the time window of spike-timing dependent plasticity in the cortex. Moreover, we found that repeated retrieval of a stored association leads to a compression of the interval between cue presentation and retrieval of the associated pattern from the cortex. Neither a high degree of connectivity nor heterogenous synaptic delays alone is sufficient for this behavior. We conclude that basic anatomical properties between cortex and hippocampus implement mechanisms for representing and consolidating temporal information. Since our model reveals the observed functions for a range of parameters, we suggest that these functions are robust to evolutionary changes consistent with the preserved function of the hippocampal loop across different species.     

iTRAQ-Based Quantitative Proteomics Suggests Synaptic Mitochondrial Dysfunction in the Hippocampus of Rats Susceptible to Chronic Mild Stress

Mounting studies show that hippocampal synaptic transmission and plasticity are abnormal in depression. It has been suggested that impairment of synaptic mitochondrial functions potentially occurs in the hippocampus. Thus, the synaptic mitochondria may be a crucial therapeutic target in the course of depression. Here, we investigated the potential dysregulation of synaptic mitochondrial proteins in the hippocampus of a chronic mild stress (CMS) rat model. Proteomic changes of hippocampal synaptosomes containing synaptic mitochondria were quantitatively examined using the isobaric tag for relative and absolute quantitation labeling combined with tandem mass spectrometry. 45 Proteins were identified to be differentially expressed, of which 21 were found to be putative synaptic mitochondrial proteins based on gene ontology component and SynaptomeDB analyses. Detailed investigations of protein functions and disease relevance support the importance of hippocampal synaptic mitochondria as a key substrate contributing to impairment in synaptic plasticity of stress-related disorders. Interestingly, eight synaptic mitochondrial proteins were specifically associated to the susceptible group, and might represent part of molecular basis of depression. Further analysis indicated that the synaptic mitochondrial oxidative phosphorylation (OXPHOS) system was heavily affected by CMS in the susceptible rats. The present results provide novel insights into the disease mechanism underlying the abnormal OXPHOS that is responsible for energy-demanding synaptic plasticity, and thereby increase our understanding of the role of hippocampal synaptic mitochondrial dysfunction in depression.     

Self-Organization of Microcircuits in Networks of Spiking Neurons with Plastic Synapses

The synaptic connectivity of cortical networks features an overrepresentation of certain wiring motifs compared to simple random-network models. This structure is shaped, in part, by synaptic plasticity that promotes or suppresses connections between neurons depending on their joint spiking activity. Frequently, theoretical studies focus on how feedforward inputs drive plasticity to create this network structure. We study the complementary scenario of self-organized structure in a recurrent network, with spike timing-dependent plasticity driven by spontaneous dynamics. We develop a self-consistent theory for the evolution of network structure by combining fast spiking covariance with a slow evolution of synaptic weights. Through a finite-size expansion of network dynamics we obtain a low-dimensional set of nonlinear differential equations for the evolution of two-synapse connectivity motifs. With this theory in hand, we explore how the form of the plasticity rule drives the evolution of microcircuits in cortical networks. When potentiation and depression are in approximate balance, synaptic dynamics depend on weighted divergent, convergent, and chain motifs. For additive, Hebbian STDP these motif interactions create instabilities in synaptic dynamics that either promote or suppress the initial network structure. Our work provides a consistent theoretical framework for studying how spiking activity in recurrent networks interacts with synaptic plasticity to determine network structure.     

Stress,metaplasticity, and antidepressants

A large body of evidence has established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the hippocampus, result from a decrease in the expression of brain-derived neurotrophic factor (BDNF) associated with elevation of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both neuronal survival and neurogenesis, is thought to represent a converging mechanism of action of various types of antidepressant treatments (e.g., antidepressant drugs and transcranial magnetic stimulation). However, as also revealed by converging lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic connectivity ('negative' metaplasticity), whereas an increase in expression of BDNF up-regulates connectivity in the hippocampus ('positive' metaplasticity). Therefore, antidepressant treatments might not only restore cell density but also regulate higher-order synaptic plasticity in the hippocampus by abolishing 'negative' metaplasticity, and thus restore hippocampal cognitive processes that are altered by stress and in depressed patients. This antidepressant regulatory effect on hippocampal synaptic plasticity function, which may, in turn, suppress 'negative' metaplasticity in other limbic structures, is discussed.     

Target-Specific Expression of Presynaptic NMDA Receptors in Neocortical Microcircuits

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.     

Functional MRI of long-term potentiation: imaging network plasticity

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.     

Memory retention in pyramidal neurons: a unified model of energy-based homo and heterosynaptic plasticity with homeostasis

The brain can learn new tasks without forgetting old ones. This memory retention is closely associated with the long-term stability of synaptic strength. To understand the capacity of pyramidal neurons to preserve memory under different tasks, we established a plasticity model based on the postsynaptic membrane energy state, in which the change in synaptic strength depends on the difference between the energy state after stimulation and the resting energy state. If the post-stimulation energy state is higher than the resting energy state, then synaptic depression occurs. On the contrary, the synapse is strengthened. Our model unifies homo- and heterosynaptic plasticity and can reproduce synaptic plasticity observed in multiple experiments, such as spike-timing-dependent plasticity, and cooperative plasticity with few and common parameters. Based on the proposed plasticity model, we conducted a simulation study on how the activation patterns of dendritic branches by different tasks affect the synaptic connection strength of pyramidal neurons. We further investigate the formation mechanism by which different tasks activate different dendritic branches. Simulation results show that compare to the classic plasticity model, the plasticity model we proposed can achieve a better spatial separation of different branches activated by different tasks in pyramidal neurons, which deepens our insight into the memory retention mechanism of brains.     

Glutamatergic neurotransmission in the synapsin I and II double knock-out mouse

The synaptic vesicle-associated synapsin proteins may participate in synaptic transmission, but their exact functional role(s) here remain(s) uncertain. We here briefly describe the important characteristics of the synapsin proteins, and review recent studies on transgenic mice devoid of the gene products encoded by the synapsin I and II genes, where both neurochemical, cell biological and electrophysiological methods have been employed. We present evidence for synapsin effects on both neurotransmitter synthesis and homeostasis, as well as on synaptic vesicle development and functions. Moreover, we describe physiological analyses of excitatory glutamatergic hippocampal synapses where a novel synapsin-dependent delayed response enhancement (DRE) phase occurs, and demonstrate the postnatal developmental patterns of both frequency facilitations and DRE responses. Finally, we report synapsin I and II effects in distinct excitatory glutamatergic synapses in the hippocampus, and indicate that synapsin-dependent modulations of synaptic function may use distinct presynaptic response patterns in order to induce different classes of presynaptic plasticity.     

Efficient Transmission of Subthreshold Signals in Complex Networks of Spiking Neurons

We investigate the efficient transmission and processing of weak, subthreshold signals in a realistic neural medium in the presence of different levels of the underlying noise. Assuming Hebbian weights for maximal synaptic conductances—that naturally balances the network with excitatory and inhibitory synapses—and considering short-term synaptic plasticity affecting such conductances, we found different dynamic phases in the system. This includes a memory phase where population of neurons remain synchronized, an oscillatory phase where transitions between different synchronized populations of neurons appears and an asynchronous or noisy phase. When a weak stimulus input is applied to each neuron, increasing the level of noise in the medium we found an efficient transmission of such stimuli around the transition and critical points separating different phases for well-defined different levels of stochasticity in the system. We proved that this intriguing phenomenon is quite robust, as it occurs in different situations including several types of synaptic plasticity, different type and number of stored patterns and diverse network topologies, namely, diluted networks and complex topologies such as scale-free and small-world networks. We conclude that the robustness of the phenomenon in different realistic scenarios, including spiking neurons, short-term synaptic plasticity and complex networks topologies, make very likely that it could also occur in actual neural systems as recent psycho-physical experiments suggest.     

Interneuron networks in the hippocampus

The hippocampus has contributed enormously to our understanding of the operation of elemental brain circuits, not least through the classification of forebrain interneurons. Understanding the operation of interneuron networks however requires not only a wiring diagram that describes the innervation and postsynaptic targets of different GABAergic cells, but also an appreciation of the temporal dimension. Interneurons differ extensively in their intrinsic firing rates, their recruitment in different brain rhythms, and in their synaptic kinetics. Furthermore, in common with principal neurons, both the synapses innervating interneurons and the synapses made by these cells are highly modifiable, reflecting both their recent or remote use (short-term and long-term plasticity) and the action of extracellular messengers. This review examines recent progress in understanding how different hippocampal interneuron networks contribute to feedback and feed-forward inhibition at different timescales.     

Emergence of preferred firing sequences in large spiking neural networks during simulated neuronal development

Two main processes concurrently refine the nervous system over the course of development: cell death and selective synaptic pruning. We simulated large spiking neural networks (100 x 100 neurons "at birth") characterized by an early developmental phase with cell death due to excessive firing rate, followed by the onset of spike timing dependent synaptic plasticity (STDP), driven by spatiotemporal patterns of stimulation. The cell death affected the inhibitory units more than the excitatory units during the early developmental phase. The network activity showed the appearance of recurrent spatiotemporal firing patterns along the STDP phase, thus suggesting the emergence of cell assemblies from the initially randomly connected networks. Some of these patterns were detected throughout the simulation despite the activity-driven network modifications while others disappeared.     

Effect of stimulus-driven pruning on the detection of spatiotemporal patterns of activity in large neural networks

Adult patterns of neuronal connectivity develop from a transient embryonic template characterized by exuberant projections to both appropriate and inappropriate target regions in a process known as synaptic pruning. Trigger signals able to induce synaptic pruning could be related to dynamic functions that depend on the timing of action potentials. We stimulated locally connected random networks of spiking neurons and observed the effect of a spike-timing-dependent synaptic plasticity (STDP)-driven pruning process on the emergence of cell assemblies. The spike trains of the simulated excitatory neurons were recorded. We searched for spatiotemporal firing patterns as potential markers of the build-up of functionally organized recurrent activity associated with spatially organized connectivity.     

孕期地塞米松暴露对大鼠子代海马神经元增殖以及突触可塑性的影响

地塞米松是一种糖皮质激素药物,具有抗炎、抑制免疫等多种药理作用,广泛应用于治疗多种疾病。临床上常使用地塞米松来促进早产儿的肺成熟以及预防胎儿呼吸窘迫综合征。目前的流行病学以及试验研究表明,地塞米松孕期暴露会增加子代患软骨病、肾脏损伤等疾病的风险。为了探究孕期地塞米松暴露(prenatal dexamethasone exposure,PDE)对大鼠子代胎鼠海马神经元增殖发育以及胎鼠海马突触可塑性形成的影响,对孕中晚期Wistar大鼠皮下注射地塞米松(0.2 mg·kg^-1·d^-1),对照组注射等剂量0.9%氯化钠溶液。收集GD20子代海马,采用实时荧光定量PCR以及Western blot法对海马神经增殖、突触可塑性形成和APPL1(adaptor protein containing pH domain,PTB domain and leucine zipper motif 1)进行相关功能检测,并进一步使用投射电镜观察海马突触超微结构。结果显示,与空白对照组相比,PDE胎海马Ki67、增殖细胞核抗原(proliferating cell ...