Term Synaptic Plasticity Research Articles

Study on the Role of Physical Fields in TMAS to Modulate Synaptic Plasticity in Mice.

Transcranial magneto-acoustic stimulation (TMAS) is a composite technique combining static magnetic and coupled electric fields with transcranial ultrasound stimulation (TUS) and has shown advantages in neuromodulation. However, the role of these physical fields in neuromodulation is unclear. Synaptic plasticity is the cellular basis for learning and memory. In this paper, we varied the intensity of static magnetic, electric and ultrasonic fields respectively to investigate the modulation of synaptic plasticity by these physical fields. There are control, static magnetic field (0.1 T/0.2 T), TUS (0.15/0.3 MPa), and TMAS (0.15 MPa + 0.2 V/m, 0.3 MPa + 0.2 V/m, 0.3 MPa + 0.4 V/m) groups. Hippocampal areas were stimulated at 5 min daily for 7 days and in vivo electrophysiological experiments were performed. TMAS induced greater LTP, LTD, and paired-pulse ratio (PPR) than TUS, reflecting that TMAS has a more significant modulation in both long- and short- term synaptic plasticity. In TMAS, a doubling of the electric field amplitude increases LTP, LTD and PPR to a greater extent than a doubling of the acoustic pressure. Increasing the static magnetic field intensity has no significant effect on the modulation of synaptic plasticity. This paper argues that electric fields should be the main reason for the difference in modulation between TMAS and TUS and that changing the amplitude of the electric field affected the modulation of TMAS more than changing the acoustic pressure. This study elucidates the roles of the physical fields in TMAS and provides a parameterisation way to guide TMAS applications based on the dominant roles of the physical fields.

Theta-gamma phase amplitude coupling in a hippocampal CA1 microcircuit.

Phase amplitude coupling (PAC) between slow and fast oscillations is found throughout the brain and plays important functional roles. Its neural origin remains unclear. Experimental findings are often puzzling and sometimes contradictory. Most computational models rely on pairs of pacemaker neurons or neural populations tuned at different frequencies to produce PAC. Here, using a data-driven model of a hippocampal microcircuit, we demonstrate that PAC can naturally emerge from a single feedback mechanism involving an inhibitory and excitatory neuron population, which interplay to generate theta frequency periodic bursts of higher frequency gamma. The model suggests the conditions under which a CA1 microcircuit can operate to elicit theta-gamma PAC, and highlights the modulatory role of OLM and PVBC cells, recurrent connectivity, and short term synaptic plasticity. Surprisingly, the results suggest the experimentally testable prediction that the generation of the slow population oscillation requires the fast one and cannot occur without it.

Structural Engineering of H0.5Z0.5O2‐Based Ferroelectric Tunneling Junction for Fast‐Speed and Low‐Power Artificial Synapses

AbstractAdvanced synaptic devices capable of neuromorphic data processing are widely studied as the building block in the next‐generation computing architecture for artificial intelligence applications. Due to its fast speed, low power, and excellent complementary metal‐oxide‐semiconductor (CMOS) compatibility, Zr‐doped HfO2 (HZO)‐based ferroelectric tunnel junction (FTJ) are promising candidates as a new type of non‐volatile memory for neuromorphic device applications. Here, an experimental approach is reported to enhance the tunneling efficiency and the electrical performance by engineering the dielectric stack of the FTJ device. By sandwiching the HZO ferroelectric layer with ZrO2 and Al2O3 layers, the FTJ tunneling current is greatly increased with lowered barrier, larger remnant polarization (Pr), and tunneling electrical resistance ratio as well as suppressed leakage current have been achieved. The optimized FTJ devices are further implemented emulating synaptic functions with demonstrated short/long‐term synaptic plasticity and spike‐timing‐dependent plasticity behaviors. Such engineering in HZO‐based FTJ devices can be promising and instructive for the realization of future ultra‐low‐power and CMOS‐compatible neuromorphic devices and systems.

The role of glial glutamate transporter in the baseline synaptic response and short-term synaptic plasticity of CA1 area of the hippocampus in male Wistar rat

Background. Glial cells release different gliotransmitters and response to neurotransmitters released from neurons. These cells especially astrocytes, having different transporters, play an important role in synaptic space homeostasis and synaptic plasticity. In this study, the role of hippocampal glial glutamate transporter (EAAT2) in baseline synaptic response and short term synaptic plasticity were investigated. Methods. In this experimental study, ceftriaxone, EAAT2 activator (0.5mmol/0.5μl), was microinjected intrahippcampally for activation of hippocampal glial glutamate transporter in male wistar rats. Baseline synaptic response and short term synaptic plasticity were evaluated by field potential recording. fEPSP was recorded from CA1 following Schaffer collaterals stimulation. After Input/Output curve construction, short term synaptic plasticity was induced by paired pulse stimulations. Results. Activation of EAAT2 by ceftriaxone microinjection in CA1 did not have any effect on baseline synaptic response (P> 0.05, Two Way ANOVA). There was no significant difference in Paired Pulse Index at 20, 80, and 200 ms inter-pulse interval between ceftriaxone treated and control group (P> 0.05, Two Way ANOVA). Conclusion. The results suggest that hippocampal glial glutamate transporter activation does not have effect on baseline synaptic response and short term synaptic plasticity in CA1 area of the hippocampus. Practical implications. Considering the role of glial cells in regulating the excitability of the nervous system as well as synaptic plasticity, correcting these features of the nervous system by manipulating glial cells can help the treatment or prevention of neurological diseases. In this study, the role of glial cells in the homeostasis of the glutamate in the synaptic space of the hippocampus was evaluated, through the stimulation of its uptake, on the basic synaptic activity and short-term synaptic plasticity.

Overexpression of protein kinase Mζ in the hippocampal dentate gyrus rescues amyloid-β-induced synaptic dysfunction within entorhinal-hippocampal circuit

Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (Aβ) impair synaptic transmission in experimental AD models. Protein kinase Mζ (PKMζ) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKMζ overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric Aβ 1-42 (oAβ) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 µL of lentiviral vector (~108 TU/mL) encoding PKMζ genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKMζ overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKMζ ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKMζ inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKMζ on synaptic activity and memory performance. PKMζ-dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD.

The Minocycline Ameliorated the Synaptic Plasticity Impairment in Vascular Dementia.

Chronic cerebral hypoperfusion (CCH) leads to vascular dementia with progressive hippocampal damage and cognitive impairments. In the present study, we compared early and late Minocycline (MINO) treatment on cognitive function, long and short-term synaptic-plasticity following CCH. We used bilateral common carotid arteries occlusion model (2VO) for induction of hypoperfusion. Male Sprague-Dawley rats were divided into 5 following groups (each having 2 subgroups): 2VO + V (vehicle), 2VO+MINO-E (early treatment of MINO on days 0 to 3 after 2VO), 2VO+MINO-L (late-treatment on days 21 to 32 after 2VO), control, and sham. Passive-avoidance (PA) and radial arm maze (RAM) tests were used to investigate learning and memory. Long term and short term synaptic plasticity were assessed by field potential recording, the brains were removed after recording and preserved for histological study to count pyramidal cells in CA1 region.Cerebral hypoperfusion could impair memory performance, synaptic plasticity, and basal synaptic transmission (BST) along with hippocampal cell loss. Thus, we found a significant reduction in step-through latency (STL) of PA test with a higher number of working and reference errors in RAM in CCH rats. However, only late treatment with MINO improved memory performance, synaptic plasticity, hippocampal cell loss, and increased neurotransmitter pool (NP) in CCH rats, but early treatment could not produce long-lasting beneficial effects 32 days after 2VO. MINO may improve synaptic plasticity and memory performance in hypo-perfused rats directly and indirectly by increasing NP and/or suppressing inflammatory factors, respectively.

Synaptic Plasticity and its Modulation byAlcohol.

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

Target-wide Induction and Synapse Type-Specific Robustness of Presynaptic Homeostasis.

Presynaptic homeostatic plasticity (PHP) is an evolutionarily conserved form of adaptive neuromodulation and is observed at both central and peripheral synapses. In this work, we make several fundamental advances by interrogating the synapse specificity of PHP. We define how PHP remains robust to acute versus long-term neurotransmitter receptor perturbation. We describe a general PHP property that includes global induction and synapse-specific expression mechanisms. Finally, we detail a novel synapse-specific PHP expression mechanism that enables the conversion from short- to long-term PHP expression. If our data can be extended to other systems, including the mammalian central nervous system, they suggest that PHP can be broadly induced and expressed to sustain the function of complex neural circuitry.

Temporary inactivation of interpeduncular nucleus impairs long but not short term plasticity in the perforant-path dentate gyrus synapses in rats

The interconnectivity of the hippocampus, interpeduncular nucleus (IPN) and several brain structures which are involved in modulating hippocampal theta rhythm activity makes a complicated dynamic network of interconnected regions and highlights the role of IPN in the hippocampal dependent learning and memory. In the present study we aimed to address whether IPN is involved in the perforant path-dentate gyrus (PPDG) short term and long term synaptic plasticity in rats. To silent IPN transiently, lidocaine was injected through the implanted cannula above the IPN. To evaluate short term plasticity, paired pulses stimulation of PPDG synapses were used upon IPN temporary inactivation. Furthermore, long term plasticity was investigated by measuring the induction and maintenance of PPDG synapses long term potentiation (LTP) after high frequency stimulation (HFS) of the mentioned pathway following to IPN inactivation. The results showed that IPN reversible inactivation had no effect on short term plasticity of PPDG synapses. However, IPN inactivation before the PPDG high frequency stimulation could significantly suppress both the population spike (PS) and fEPSP-LTP induction compared to the saline group. Conversely, IPN inactivation had no significant effect on maintenance of both PS-LTP and fEPSP-LTP. All together our study suggests the contribution of IPN in the PPDG synaptic plasticity and excitability of DG granule cells which could be through direct and/or indirect pathways from IPN to the hippocampus.

Intermittent Hypoxia Disrupts Synaptic Long Term Depression

Long term potentiation (LTP), activity‐dependent synaptic strengthening, and long term depression (LTD), activity dependent synaptic attenuation, are two forms of synaptic plasticity whose underlying mechanisms permit flexibility in synaptic communication and serve as substrates for learning and memory. Intermittent hypoxia (IH), a hallmark of sleep apnea, is known to impair spatial learning and memory. The objective of this study is determine how LTP and LTD are affected by IH. We hypothesize that IH impedes efficacy of activity dependent synaptic plasticity in the hippocampus, a brain structure important to learning and memory. We examined in vitro LTP and LTD in hippocampal brain slices following IH exposure. Electrophysiological recordings showed that LTP in area CA1 could be evoked in control and IH exposed groups, yet the magnitude of LTP following IH was decreased (LTP: control 184.72±15.93% vs. IH 145.35±6.34% baseline) . While LTD could be elicited in the control group (63.31±3.03% baseline), LTD could not be evoked from the IH exposed group (104.18±3.44% baseline). Although IH impacted both forms of long term synaptic plasticity, this was not accompanied by differences in paired‐pulse facilitation, indicating that short‐term plasticity was unaffected by IH. These findings demonstrate that IH affects mechanisms of activity‐dependent regulation of synaptic efficacy, which may involve IH‐dependent changes in NMDA receptor contribution to these phenomena. Our findings further contribute to understanding potential neurophysiological changes that may decrease the threshold for cognitive decline associated with sleep apnea.Support or Funding InformationThis work was supported by NIH R01 NS10742101 (AJG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Flexible, Conformal Organic Synaptic Transistors on Elastomer for Biomedical Applications

AbstractBioelectronics in synaptic transistors for future biomedical applications, such as implanted treatments and human–machine interfaces, must be flexible with good mechanical compatibility with biological tissues. The rigid nature and high deposition temperature in conventional inorganic synaptic transistors restrict the development of flexible, conformal synaptic devices. Here, the dinaphtho[2,3‐b:2′,3′‐f]thieno[3,2‐b]‐thiophene organic synaptic transistor on elastic polydimethylsiloxane is demonstrated to avoid these limitations. The unique advantages of organic materials in low Young's modulus and low temperature process enable seamless adherence of organic synaptic transistors on arbitrary‐shaped objects. On 3D curved surfaces, the essential synaptic functions, such as potentiation/depression, short/long‐term synaptic plasticity, and spike voltage–dependent plasticity, are successfully realized. The time‐dependent surface potential characterization reveals the slow polarization of dipoles in the dielectric is responsible for hysteresis and synaptic behaviors. This work represents that organic materials offer a potential platform to realize the flexible, conformal synaptic transistors for the development of wearable and implantable artificial neuromorphic systems.

Molecular mechanisms that stabilize short term synaptic plasticity during presynaptic homeostatic plasticity.

Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super-primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse.

Data Driven Models of Short-Term Synaptic Plasticity.

Simple models of short term synaptic plasticity that incorporate facilitation and/or depression have been created in abundance for different synapse types and circumstances. The analysis of these models has included computing mutual information between a stochastic input spike train and some sort of representation of the postsynaptic response. While this approach has proven useful in many contexts, for the purpose of determining the type of process underlying a stochastic output train, it ignores the ordering of the responses, leaving an important characterizing feature on the table. In this paper we use a broader class of information measures on output only, and specifically construct hidden Markov models (HMMs) (known as epsilon machines or causal state models) to differentiate between synapse type, and classify the complexity of the process. We find that the machines allow us to differentiate between processes in a way not possible by considering distributions alone. We are also able to understand these differences in terms of the dynamics of the model used to create the output response, bringing the analysis full circle. Hence this technique provides a complimentary description of the synaptic filtering process, and potentially expands the interpretation of future experimental results.

Sulfamethoxazole induces zinc changes at hippocampal mossy fiber synapses from pregnant rats.

The accumulation of intracellular ionic zinc and pharmaceutical compounds, like the antibiotic sulfamethoxazole, may contribute to various neuropathologies. Sulfamethoxazole and the drug trimethoprim, are inhibitors of enzymes involved in the synthesis of tetrahydrofolate and also of carbonic anhydrases. The inhibition of the latter enzymes, which are localized both intra- and extracellularly and have a key role in pH regulation, causes alkalinization that is associated with higher spontaneous transmitter release. Intense synaptic stimulation causes the entry of released zinc into postsynaptic neurons, through glutamate receptor channels or voltage dependent calcium channels. The aim of this study was to evaluate the effect of sulfamethoxazole (180 μM) on basal postsynaptic zinc and to compare it with that caused by two depolarizing media, containing high potassium or tetraethylammonium, which may induce long term synaptic plasticity. The studies were performed in brain slices from gestating rats, at the mossy fiber synapses from hippocampal CA3 area, using the zinc indicator Newport Green. In the presence of KCl (20 mM) and sulfamethoxazole (180 μM) the zinc signals were enhanced, unlike in tetraethylammonium (25 mM). After sulfamethoxazole the tetraethylammonium evoked zinc signal had reduced amplitude. Thus, the data suggests that sulfamethoxazole enhances transmitter release affecting synaptic zinc physiology.

Positive feedback and synchronized bursts in neuronal cultures.

Synchronized bursts (SBs) with complex structures are common in neuronal cultures. Although the phenomenon of SBs has been discovered for a long time, its origin is still unclear. Here, we investigate the properties of these SBs in cultures grown on a multi-electrode array. We find that structures of these SBs are related to the different developmental stages of the cultures and these structures can be modified by changing the magnesium concentration in the culture medium; indicating that synaptic mechanism is involved in the generation of SBs. A model based on short term synaptic plasticity (STSP), recurrent connections and astrocytic recycling of neurotransmitters has been developed successfully to understand the observed structures of SBs in experiments. A phase diagram obtained from this model shows that networks exhibiting SBs are in a complex oscillatory state due to large enough positive feedback provided by synaptic facilitation and recurrent connections. In this model, while STSP controls the fast oscillations (∼ 100 ms) within a SB, the astrocytic recycling determines the slow time scale (∼10 s) of inter-burst intervals. Our study suggests that glia-neuron interactions can be important in the understanding of the complex dynamics of neuronal networks.

Norepinephrine (NE) and intermittent hypoxia (IH) impact short term synaptic plasticity in the hippocampus

Conditions such as sleep apnea can produce states of increased noradrenergic tone that coincide with bouts of IH. A previous report indicates that the influence of IH on neurophysiology is changed by increased noradrenergic tone. The objective of this ongoing study is to determine how acute IH (AIH) and NE affect short‐term synaptic plasticity (i.e., paired pulse facilitation, PPF) in the CA1 neuronal population. We hypothesize that NE changes PPF following AIH. To test this hypothesis, extracellular recordings of electrically evoked field excitatory postsynaptic potentials were made from the CA1 neuronal population within mouse hippocampal brain slices. A paired pulse protocol using an interpulse interval (20ms to 500ms) was performed before and following AIH. AIH consisted of three intervals of hypoxia (95% N2, duration=180 sec) separated by recovery periods (95% O2, duration=180 sec). While 2 mircoM NE did not affect PPF (n=3), PPF was augmented following AIH (n=4). However, combined, NE/AIH suppressed PPF (n=3). Our findings, to date, suggest that NE alters how IH affects short term plasticity in the CA1 neuronal population.

Co-injection of Aβ1-40 and ApoE4 impaired spatial memory and hippocampal long-term potentiation in rats

Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimer’s disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Aβ)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Aβ1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Aβ1-40 and ApoE4, and investigated the effects of co-application of Aβ1-40 and ApoE4 on cognitive behavior and synaptic plasticity. The results showed that intracerebrovenrticular (i.c.v.) injection of Aβ1-40 or ApoE4 significantly and similarly impaired spatial learning and memory, and depressed the high-frequency stimulus (HFS) induced LTP. Importantly, compared to the effects of Aβ1-40 or ApoE4 alone, co-injection of Aβ1-40 and ApoE4 produced much heavier damages in cognitive behaviors and long term synaptic plasticity. These results demonstrated that ApoE4 not only exerted direct neurotoxicity but also enhanced the neurotoxicity of Aβ1-40 on spatial cognitive function and hippocampal LTP, which maybe partly elucidates the mechanism by which APOE4 allele exerted negative effects as a major genetic risk factor for developing AD.

Synchronization and long-time memory in neural networks with inhibitory hubs and synaptic plasticity.

We investigate the dynamical role of inhibitory and highly connected nodes (hub) in synchronization and input processing of leaky-integrate-and-fire neural networks with short term synaptic plasticity. We take advantage of a heterogeneous mean-field approximation to encode the role of network structure and we tune the fraction of inhibitory neurons f_{I} and their connectivity level to investigate the cooperation between hub features and inhibition. We show that, depending on f_{I}, highly connected inhibitory nodes strongly drive the synchronization properties of the overall network through dynamical transitions from synchronous to asynchronous regimes. Furthermore, a metastable regime with long memory of external inputs emerges for a specific fraction of hub inhibitory neurons, underlining the role of inhibition and connectivity also for input processing in neural networks.

Models of Short-Term Synaptic Plasticity.

We focus on dynamical descriptions of short-term synaptic plasticity. Instead of focusing on the molecular machinery that has been reviewed recently by several authors, we concentrate on the dynamics and functional significance of synaptic plasticity, and review some mathematical models that reproduce different properties of the dynamics of short term synaptic plasticity that have been observed experimentally. The complexity and shortcomings of these models point to the need of simple, yet physiologically meaningful models. We propose a simplified model to be tested in synapses displaying different types of short-term plasticity.

Effect of applied current on sub-thalamic neuron

This paper describes the electrophysiological properties of the neurons within the STN. Inhibitory and excitatory inputs are given to an oval shaped small nucleus called STN. Short term synaptic plasticity could be one of the methods for repetitive simulation that evokes strong modulations of globus pallidus (GP) activity. Parkinsonism get synchronised with the firing of STN neurons and two types of external GP neuron. For analysis and study of synaptic current IG→S, an applied current Iapp is used and worked with different values of it. The result of the model will be compared and listed with the experimental results. Different values of applied current are taken which shows the relation with membrane conductance. The work is done on MATLAB R2014a tool Version 8.3.