Various Forms Of Synaptic Plasticity Research Articles

Phosphorylation of tau protein based on the activity of kinases and phosphatases in various forms of synaptic plasticity.

The aim of this study is to show the relationship between the change in the strengthening of synaptic plasticity and tau phosphorylation and tau-kinases and phosphatase. The averages of the field excitatory-postsynaptic potential (fEPSP) and population spike (PS) in the last 5 min were used as a measure of LTP, LTD and MP. Total and phosphorylated levels of tau, kinases and phosphatases were evaluated by western blot and mRNA levels were evaluated by RT-qPCR. The stimulation of synapses by HFS and LFS+HFS increased the phosphorylation of total-tau and phospho-tau at the Thr181, Ser202/Thr205, Ser396 and Ser416 residues, and these were accompanied by increased enzymatic activity of Akt, ERK1/2. Theincreased phosphorylation of tau may mediate maintenance of LTP. If the increase in phosphorylation of tau cannot be prevented, together with inhibition of the subsequent LTP, this may indicate that the physiological role of hyperphosphorylated tau in synaptic plasticity may extend to pathological processes.

Estimating the Ca2+ Block of NMDA Receptors with Single-Channel Electrophysiology.

In vertebrate central neurons, NMDA receptors are glutamate- and glycine-gated ion channels that allow the passage of Na+ and Ca2+ ions into the cell when these neurotransmitters are simultaneously present. The passage of Ca2+ is critical for initiating the cellular processes underlying various forms of synaptic plasticity. These Ca2+ ions can autoregulate the NMDA receptor signal through multiple distinct mechanisms to reduce the total flux of cations. One such mechanism is the ability of Ca2+ ions to exclude the passage of Na+ ions resulting in a reduced unitary current conductance. In contrast to the well-characterized Mg2+ block, this "channel block" mechanism is voltage-independent. In this chapter, we discuss theoretical and experimental considerations for the study of channel block by Ca2+ using single-channel patch-clamp electrophysiology. We focus on two classic methodologies to quantify the dependence of unitary channel conductance on external concentrations of Ca2+ as the basis for quantifying Ca2+ block.

An Efficient Design of TaOx‐Based Memristor by Inserting an Ultrathin Al2O3 Layer with High Stability for Neuromorphic Computing and Logic Operation

AbstractNew computing‐in‐memory architecture based on memristors can achieve in situ storage and computing of data, which greatly improves the computing efficiency of the hardware system. Here, a reliable bilayer structured TaOx/Al2O3 memristor with a 2 nm Al2O3 insertion layer is demonstrated. This device exhibits stable and gradual switching behavior with a low set/reset voltage (0.61 V/−0.49 V) and multilevel conductance characteristics. It is further indicated that the device has a larger ON/Off ratio (≈148×) and better nonlinearity of conductance modulation by inserting an Al2O3 layer. Various forms of synaptic plasticity are mimicked, such as long‐term potentiation/depression (LTP/LTD), paired‐pulse facilitation (PPF), and spike‐timing‐dependent plasticity (STDP). Based on the quasi‐linear conductance modulation characteristics, excellent classification accuracy (90.4%) is achieved for the applications of handwritten digit recognition. Moreover, the logic operations (intersection, union, and complement) are implemented on a 3 × 5 memristor array, which shows an efficient way to design versatile and reliable devices and provides a novel idea for neuromorphic computing and in‐memory logic operation.

Development of Cerebellar Reserve

The cerebellar reserve is defined as the capacity of the cerebellum for compensation and restoration following injury. This unique cerebellar ability is attributed to various forms of synaptic plasticity that incorporate multimodal and redundant cerebellar inputs, two major features of the cerebellar circuitry. It is assumed that the cerebellar reserve is acquired from the age of 12 years after the maturation of both the cerebellar adaptative behaviors and cerebellar functional connectivity. However, acquiring the cerebellar reserve is also affected by two other factors: vulnerability and growth potential in the developing cerebellum. First, cerebellar injury during the critical period of neural circuit formation (especially during fetal and neonatal life and infancy) leads to persistent dysfunction of the cerebellum and its targets, resulting in the limitation of the cerebellar reserve. Secondly, growth potential appears to facilitate cerebellar reserve during the stage when the cerebellar reserve is still immature. Based on these findings, the present mini-review proposes a possible developmental trajectory underlying the acquisition of cerebellar reserve. We highlight the importance of studies dedicated to the understanding of the cerebellar resilience to injuries.

Tau-Induced Elevation of the Activity-Regulated Cytoskeleton Associated Protein Arc1 Causally Mediates Neurodegeneration in the Adult Drosophila Brain

Alzheimer’s disease and other tauopathies are neurodegenerative disorders pathologically defined by aggregated forms of tau protein in the brain. While synaptic degradation is a well-established feature of tau-induced neurotoxicity, the underlying mechanisms of how pathogenic forms of tau drive synaptic dysfunction are incompletely understood. Synaptic function and subsequent memory consolidation are dependent upon synaptic plasticity, the ability of synapses to adjust their structure and strength in response to changes in activity. The activity regulated cytoskeleton associated protein ARC acts in the nucleus and at postsynaptic densities to regulate various forms of synaptic plasticity. ARC harbors a retrovirus-like Gag domain that facilitates ARC multimerization and capsid formation. Trans-synaptic transfer of RNA-containing ARC capsids is required for synaptic plasticity. While ARC is elevated in brains of patients with Alzheimer’s disease and genetic variants in ARC increase susceptibility to Alzheimer’s disease, mechanistic insight into the role of ARC in Alzheimer’s disease is lacking. Using a Drosophila model of tauopathy, we find that pathogenic tau significantly increases multimeric species of the protein encoded by the Drosophila homolog of ARC, Arc1, in the adult fly brain. We find that Arc1 is elevated within nuclei and the neuropil of tau transgenic Drosophila, but does not localize to synaptic vesicles or presynaptic terminals. Lastly, we find that genetic manipulation of Arc1 modifies tau-induced neurotoxicity, suggesting that tau-induced Arc1 elevation mediates neurodegeneration. Taken together, our results suggest that ARC elevation in human Alzheimer’s disease is a consequence of tau pathology and is a causal factor contributing to neuronal death.

Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine.

The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.

Imaging dendritic spines: molecular organization and signaling for plasticity.

The structural plasticity of dendritic spines is considered to be essential for various forms of synaptic plasticity and, ultimately, learning and memory. The process is mediated by signaling pathways that promote the reorganization of the actin cytoskeleton and subsynaptic structures, which in turn cause structural and functional changes in dendritic spines. Recent advances in optical technologies have started to reveal the fine molecular structures and dynamic signaling occurring inside spines, providing significant insights into the molecular regulation of spines. Here, we highlight recent studies to resolve the molecular mechanisms underlying the spine actin cytoskeleton and plasticity with high spatiotemporal resolution. Moreover, we discuss new genome editing-based approaches in imaging the molecular structure and plasticity of dendritic spines.

Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Maintenance Association between Environmental Cues and Rewarding Properties of Ethanol in Rats

Metabotropic glutamate subtype 5 (mGlu5) receptors are implicated in various forms of synaptic plasticity, including drugs of abuse. In drug-addicted individuals, associative memories can drive relapse to drug use. The present study investigated the potential of the mGlu5 receptor positive allosteric modulator (PAM), VU-29 (30 mg/kg, i.p.), to inhibit the maintenance of a learned association between ethanol and environmental context by using conditioned place preference (CPP) in rats. The ethanol-CPP was established by the administration of ethanol (1.0 g/kg, i.p. ×10 days) using an unbiased procedure. Following ethanol conditioning, VU-29 was administered at various post-conditioning times (ethanol free state at the home cage) to ascertain if there was a temporal window during which VU-29 would be effective. Our experiments indicated that VU-29 did not affect the expression of ethanol-induced CPP when it was given over two post-conditioning days. However, the expression of ethanol-CPP was inhibited by 10-day home cage administration of VU-29, but not by first 2-day or last 2-day injection of VU-29 during the 10-day period. These findings reveal that VU-29 can inhibit the maintenance of ethanol-induced CPP, and that treatment duration contributes to this effect of VU-29. Furthermore, VU-29 effect was reversed by pretreatment with either MTEP (the mGlu5 receptor antagonist), or MK-801 (the N-methyl-D-aspartate-NMDA receptor antagonist). Thus, the inhibitory effect of VU-29 is dependent on the functional interaction between mGlu5 and NMDA receptors. Because a reduction in ethanol-associated cues can reduce relapse, mGlu5 receptor PAM would be useful for therapy of alcoholism. Future research is required to confirm the current findings.

Role of the TRPC1 Channel in Hippocampal Long-Term Depression and in Spatial Memory Extinction.

Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that are believed to underlie declarative memory. We previously showed that mGluR5 specifically activates channels containing TRPC1, an isoform of the canonical family of Transient Receptor Potential channels highly expressed in the CA1-3 regions of the hippocampus. Using a tamoxifen-inducible conditional knockout model, we show here that the acute deletion of the Trpc1 gene alters the extinction of spatial reference memory. mGluR-induced long-term depression, which is partially responsible for memory extinction, was impaired in these mice. Similar results were obtained in vitro and in vivo by inhibiting the channel by its most specific inhibitor, Pico145. Among the numerous known postsynaptic pathways activated by type I mGluR, we observed that the deletion of Trpc1 impaired the activation of ERK1/2 and the subsequent expression of Arc, an immediate early gene that plays a key role in AMPA receptors endocytosis and subsequent long-term depression.

Ca2+/Calmodulin Binding to PSD-95 Downregulates Its Palmitoylation and AMPARs in Long-Term Depression.

AMPA-type glutamate receptors (AMPARs) are clustered into functional nanodomains at postsynaptic sites through anchorage by the scaffolding protein, postsynaptic density protein-95 (PSD-95). The synaptic abundance of AMPARs is dynamically controlled in various forms of synaptic plasticity. Removal of AMPARs from the synapse in long-term depression (LTD) requires mobilization of PSD-95 away from the synapse. The molecular mechanisms underlying PSD-95 dispersal from the synapse during LTD are not completely understood. Here we show that, following Ca2+ influx, binding of Ca2+/calmodulin (CaM) to PSD-95 triggers loss of synaptic PSD-95 as well as surface AMPARs during chemically induced LTD in cultured rat neurons. Our data suggest that a reduction in PSD-95 palmitoylation mediates the effect of Ca2+/CaM on PSD-95 synaptic levels during LTD. These findings reveal a novel molecular mechanism for synaptic AMPAR regulation in LTD.

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity.

Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.

Emulating dynamic synaptic plasticity over broad timescales with memristive device

Memristive devices have shown great potential in realizing artificial synapses efficiently for neuromorphic computing. However, emulation of various subtle forms of plasticity over broad timescales in a single device remains a challenge. In this paper, we designed a Ag/MgO/Pt memristive device exhibiting a volatile switching behavior and demonstrated various forms of synaptic plasticity from milliseconds to days in a single device. The volatile behaviors are owing to the formation and spontaneous rupture of silver nano-filaments with and without applying electrical stimuli. By manipulating the input voltage pulse strength, such as pulse amplitude, interval, and pulse number, several key features of biological synaptic plasticity including paired pulse facilitation, augmentation, post-tetanic potentiation, early long-term plasticity (LTP), and late-LTP were emulated. In addition, a reversible transition between short-term plasticity and LTP was also demonstrated. This work enables artificial synapses with rich plasticity in a single nano-device, providing a pathway to develop a large scale artificial neural network for brain inspired computing systems.

Activation of TRPC1 Channel by Metabotropic Glutamate Receptor mGluR5 Modulates Synaptic Plasticity and Spatial Working Memory.

Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms. TRPC1/4/5 complexes have recently been involved in the efficiency of synaptic transmission in the hippocampus. We therefore used a mouse model devoid of TRPC1 expression to investigate the involvement of mGluR5-TRPC1 pathway in synaptic plasticity and memory formation. Trpc1-/- mice showed alterations in spatial working memory and fear conditioning. Activation of mGluR increased synaptic excitability in neurons from WT but not from Trpc1-/- mice. LTP triggered by a theta burst could not maintain over time in brain slices from Trpc1-/- mice. mGluR-induced LTD was also impaired in these mice. Finally, acute inhibition of TRPC1 by Pico145 on isolated neurons or on brain slices mimicked the genetic depletion of Trpc1 and inhibited mGluR-induced entry of cations and subsequent effects on synaptic plasticity, excluding developmental or compensatory mechanisms in Trpc1-/- mice. In summary, our results indicate that TRPC1 plays a role in synaptic plasticity and spatial working memory processes.

Accumulation of Dense Core Vesicles in Hippocampal Synapses Following Chronic Inactivity.

The morphology and function of neuronal synapses are regulated by neural activity, as manifested in activity-dependent synapse maturation and various forms of synaptic plasticity. Here we employed cryo-electron tomography (cryo-ET) to visualize synaptic ultrastructure in cultured hippocampal neurons and investigated changes in subcellular features in response to chronic inactivity, a paradigm often used for the induction of homeostatic synaptic plasticity. We observed a more than 2-fold increase in the mean number of dense core vesicles (DCVs) in the presynaptic compartment of excitatory synapses and an almost 20-fold increase in the number of DCVs in the presynaptic compartment of inhibitory synapses after 2 days treatment with the voltage-gated sodium channel blocker tetrodotoxin (TTX). Short-term treatment with TTX and the N-methyl-D-aspartate receptor (NMDAR) antagonist amino-5-phosphonovaleric acid (AP5) caused a 3-fold increase in the number of DCVs within 100 nm of the active zone area in excitatory synapses but had no significant effects on the overall number of DCVs. In contrast, there were very few DCVs in the postsynaptic compartments of both synapse types under all conditions. These results are consistent with a role for presynaptic DCVs in activity-dependent synapse maturation. We speculate that these accumulated DCVs can be released upon reactivation and may contribute to homeostatic metaplasticity.

Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation.

Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments.

Group I Metabotropic Glutamate Receptors (mGluRs): Ins and Outs.

Glutamate is a nonessential amino acid, known to act as a major excitatory neurotransmitter in the central nervous system. Glutamate transduces its signal by activating two types of receptors, viz., ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). mGluR1 and mGluR5 are members of the group I mGluR family, and they belong to the G-protein-coupled receptor (GPCR) family. These receptors are involved in various forms of synaptic plasticity including learning and memory. Similar to many other GPCRs, trafficking plays a critical role in controlling the spatiotemporal localization of these receptors on the cell surface, which is critical for the normal ligand/receptor interaction. Improper targeting of GPCRs results in aberrant signaling, which often leads to various diseases. Trafficking also regulates the activity of these receptors. Thus, inappropriate trafficking of these receptors might have pathological consequences. Group I mGluRs have been implicated in various neuropsychiatric disorders like Fragile X syndrome, autism, etc. In this review, we discuss the current understanding of group I mGluR trafficking in the central nervous system and its physiological importance.

The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer

The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. However, little is known about Arc's molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties to retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.

Forebrain-specific, conditional silencing of Staufen2 alters synaptic plasticity, learning, and memory in rats

BackgroundDendritic messenger RNA (mRNA) localization and subsequent local translation in dendrites critically contributes to synaptic plasticity and learning and memory. Little is known, however, about the contribution of RNA-binding proteins (RBPs) to these processes in vivo.ResultsTo delineate the role of the double-stranded RBP Staufen2 (Stau2), we generate a transgenic rat model, in which Stau2 expression is conditionally silenced by Cre-inducible expression of a microRNA (miRNA) targeting Stau2 mRNA in adult forebrain neurons. Known physiological mRNA targets for Stau2, such as RhoA, Complexin 1, and Rgs4 mRNAs, are found to be dysregulated in brains of Stau2-deficient rats. In vivo electrophysiological recordings reveal synaptic strengthening upon stimulation, showing a shift in the frequency-response function of hippocampal synaptic plasticity to favor long-term potentiation and impair long-term depression in Stau2-deficient rats. These observations are accompanied by deficits in hippocampal spatial working memory, spatial novelty detection, and in tasks investigating associative learning and memory.ConclusionsTogether, these experiments reveal a critical contribution of Stau2 to various forms of synaptic plasticity including spatial working memory and cognitive management of new environmental information. These findings might contribute to the development of treatments for conditions associated with learning and memory deficits.

Kinetics of Releasable Synaptic Vesicles and Their Plastic Changes at Hippocampal Mossy Fiber Synapses

Hippocampal mossy fiber boutons (hMFBs) are presynaptic terminals displaying various forms of synaptic plasticity. The presynaptic mechanisms underlying synaptic plasticity still remain poorly understood. Here, we have combined high temporal resolution measurements of presynaptic capacitance and excitatory postsynaptic currents (EPSCs) to measure the kinetics of exocytosis. In addition, total internal reflection fluorescence (TIRF) microscopy was employed to directly visualize dynamics of single synaptic vesicles adjacent to the plasma membrane at high spatial resolution. Readily releasable vesicles mostly consisted of already-tethered vesicles in the TIRF field. Vesicle replenishment had fast and slow phases, and TIRF imaging suggests that the fast phase depends on vesicle priming from already-tethered vesicles. Application of cyclic AMP (cAMP), a molecule crucial for LTP, mainly increases the vesicular release probability rather than the number of readily releasable vesicles or their replenishment rate, likely by changing the coupling between Ca2+ channels and synaptic vesicles. Thus, we revealed dynamic properties of synaptic vesicles at hMFBs.

Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB

Arc/Arg3.1 is a unique immediate early gene whose expression is highly dynamic and correlated with various forms of synaptic plasticity. Many previous reports highlight the complexity of mechanisms that regulate Arc/Arg3.1 expression in neurons. In the present study, the expression and regulation of Arc/Arg3.1 after glutamate treatment in primary cultured cortical neurons were investigated. We found that both Arc/Arg3.1 mRNA and Arc/Arg3.1 protein dynamically increased within 24h after glutamate treatment. The results of immunostaining showed that abundant amounts of Arc/Arg3.1 protein are presented in both soma and dendrites. The glutamate-induced increase in Arc/Arg3.1 protein levels was partially prevented by the NMDAR inhibitor DL-AP5, but not the AMPAR inhibitor NBQX. The results of calcium imaging showed that glutamate induced significant increases in intracellular calcium levels in a NMDAR-dependent manner. However, the intracellular calcium chelator BAPTA-AM had no effect on glutamate-induced upregulation of Arc/Arg3.1 protein, and alteration of cytosolic calcium ion homeostasis with A23187 and TG did not change Arc/Arg3.1 protein levels. In addition, the phosphorylation of ERK and CREB, two downstream factors of NMDAR signaling, markedly increased after glutamate exposure. Blocking ERK and CREB activation via selective inhibitors partially prevented the glutamate-induced elevation of Arc/Arg3.1 protein levels. Combined observations support a NMDAR-mediated and calcium-independent mechanism by which glutamate increases Arc/Arg3.1 expression in cortical neurons.