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Alzheimer's disease (AD) is an incurable, age-related and progressive neurodegenerative disease characterized by cognitive impairments. Deficits in synaptic plasticity were reported in various models of AD-like pathology and are considered as an early contributing factor of cognitive impairment. However, the majority of previous studies were focused on overt, symptomatic stages of pathology and assessed long-term potentiation (LTP), whereas long-term depression (LTD) was much less investigated and the precise nature of its involvement remains poorly defined. To better understand the earliest synaptic dysfunctions along the pre-symptomatic stage of AD-like pathology, we performed a detailed analysis of underlying mechanisms and quantified basal synaptic activity, presynaptic release probability, and synaptic plasticity such as post-tetanic potentiation (PTP), as well as LTP and LTD. These parameters were studied in APPPS1 mouse model at two time points (early- and mid-) along the pre-symptomatic stage, which were compared with alterations monitored at two later time-points, i.e. the onset of cognitive deficits and the overt stage of full-blown pathology. Because sex is known to be an instrumental biological parameter in AD pathophysiology, all alterations were assessed in both males and females. Our data show that, as compared to wild-type (WT) littermates, initial neuronal hyperexcitability, seen at early pre-symptomatic stage shifts subsequently towards hypoexcitability at mid-pre-symptomatic stage and remains impaired at advanced stages. The pre-symptomatic changes also involve increased synaptic plasticity as assessed by paired-pulse facilitation (PPF), which returns to basal level at the onset of pathology and remains stable afterwards. Synaptic plasticity is impaired by mid-pre-symptomatic stage and manifests as lowered LTP and absence of LTD induction, the latter being reported here for the first time. Observed LTP and LTD impairments both persist in older APPPS1 mice. Remarkably, none of the observed differences was gender-dependent. Altogether, our data evidence that major impairments in basal synaptic efficacy and plasticity are detectable already during mid-pre-symptomatic stage of AD-like pathogenesis and likely involve hyperexcitability as the underlying mechanism. Our study also uncovers synaptic alterations that may become critical read-outs for testing the efficiency of novel, pre-symptomatic stage-targeted therapies for AD. • Alzheimer's Disease (AD) displays a long pre-symptomatic stage (PSS). • AD is still incurable since treated late and targeting PSS may be more efficient. • PSS is impossible to assess in human and requires models to identify early targets. • Using a mouse AD model, we identified a novel marker of PSS synaptic dysfunction. • This marker can serve as a read-out for testing efficacy of PSS-targeted therapies. [ABSTRACT FROM AUTHOR]

Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5 s for 30 min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5 ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex. In this mini-review, we briefly introduce QPS: (i) principle and cortical plasticity (stimulators and protocols, synaptic plasticity, underlying mechanisms, meta-plasticity, axonal plasticity, and drug effects), (ii) robust and strong neural plasticity induction (variability, influence of phasic muscle contraction, independency of BDNF polymorphism, sensory cortical plasticity, neural plasticity in the contralateral hemisphere, on-line effects on the brain networks, studies of normal brain physiology, and visuomotor sequence learning), (iii) therapeutic applications to neurological and psychiatric disorders (Parkinson's disease, epilepsy, cerebrovascular disease, and major depression), (iv) safety, and (v) future issues. Based on this evidence, we propose that QPS is currently the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans. [ABSTRACT FROM AUTHOR]

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity.

Highlights: [•] Can animal models be used for studying affective and cognitive comorbidities of pain? [•] How does pain interact with its comorbidities in the animals? [•] What are the underlying mechanisms of pain comorbidities in the animals? [Copyright &y& Elsevier]

Highlights: [•] Memantine rescued hippocampal-dependent memory and hippocampal LTD in JDM rats. [•] LTD was impaired by a malfunction in NR2B-containing NMDA receptors in JDM rats. [•] Abnormal NMDA receptor function was caused by excessive PKA activity in JDM rats. [Copyright &y& Elsevier]

Highlights: [•] Ca2+ permeability of synaptic AMPARs can be altered by trafficking events. [•] GluA2-lacking AMPARs are added to synapses following stimulation. [•] This occurs under specific conditions at a subset of synapses in the CNS. [•] Endosomal trafficking and lateral diffusion from perisynaptic regions are involved. [•] AMPAR interacting proteins regulate this process. [Copyright &y& Elsevier]

Highlights: [•] Aβ-enhanced hippocampal LTD depends on mGluR1/5 but not NMDAR. [•] Aβ-enhanced hippocampal LTD requires the activation of p38MAPK, PTPs and capase-3. [•] Activation of STEP is involved in Aβ-enhanced hippocampal LTD. [•] Activation of TACE and mTOR is not necessary for Aβ-enhanced hippocampal LTD. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder. [Copyright &y& Elsevier]

Abstract: Huntington’s disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease. [Copyright &y& Elsevier]

Highlights: [•] Synaptic plasticity is thought to be the underlying cellular mechanism for memory. [•] Metaplasticity describes changes that modify the properties of synaptic plasticity. [•] Behavioral metaplasticity describes plasticity changes on a more global level. [ABSTRACT FROM AUTHOR]

Abstract: The phenomenon whereby the relative timing between presynaptic and postsynaptic spiking determines the direction and extent of synaptic changes in a critical temporal window is known as spike timing-dependent synaptic plasticity (STDP). We have previously reported that STDP profiles can be classified into two types depending on their layer-specific location along CA1 pyramidal neuron dendrites in the rat hippocampus, suggesting that there are differences in information processing between the proximal dendrite (PD) and distal dendrite (DD). However, how the different types of information processing interact at different dendritic locations remains unclear. To investigate how the temporal information of inputs to PD influences information processing at DD, PD stimulation was applied while the STDP protocol was simultaneously applied at DDs of CA1 pyramidal neurons. Synaptic plasticity induced by the STDP protocol at DDs was enhanced or depressed depending on the timing of the back-propagating action potentials (bAPs) and the excitatory and inhibitory postsynaptic potentials elicited by PD stimulation. These results suggested that bAPs function as carriers of temporal information of PD inputs to DD. Next, the influence of DD on PD was investigated using the same protocol. Synaptic plasticity at PD was modulated only if the pairing stimuli were applied to elicit coincidental timing of bAP and the excitatory postsynaptic potential. Such coding modulations could provide the basis for a novel learning rule and may be important factors in the integration of spatiotemporal input information in neural networks in the brain. [Copyright &y& Elsevier]

Abstract: Objective: Low-frequency stimulation, which does not induce long-term potentiation (LTP) or long-term potentiation (LTD) by itself, suppresses consecutive LTP or LTD induction in vitro. We tested whether a similar interaction occurs in the human motor cortex. Methods: LTP- or LTD-like plasticity was induced using paired associative stimulation (PAS) with 25 and 10ms interstimulus interval and conditioned by suprathreshold repetitive transcranial magnetic stimulation (rTMS) at a frequency of 0.1Hz. Results: RTMS completely abolished the significant increase of motor-evoked potential (MEP) amplitudes after PAS25ms (PAS25ms only: 1.05±0.14 to 1.76±0.66mV, p =0.001; rTMS+PAS25ms: 1.08±0.18 to 1.02±0.44mV, n.s.) and also abolished the significant decrease of MEP amplitudes after PAS10ms (PAS10ms only: 1.00±0.14 to 0.73±0.32mV; rTMS+PAS10ms: 1.15±0.35 to 1.25±0.43mV, p =0.006). RTMS alone did not significantly alter MEP amplitudes but increased SICI and LICI. Conclusions: Low frequency stimulation increases intracortical inhibition and occludes LTP- and LTD-like plasticity in the human motor cortex. Significance: This finding supports the concept that metaplasticity in the human motor cortex follows similar rules as metaplasticity in in vitro experiments. [Copyright &y& Elsevier]

Abstract: The hippocampus communicates with the neocortex via the entorhinal cortex. These areas are thought to be critically involved in the consolidation of memories. The hippocampus is considered to be the site of association of sensory information, which is then laid down for long-term storage in the neocortex. We examined the projection from the subiculum to the entorhinal cortex to determine whether it could function to transfer this hippocampally-processed information to the neocortex. Following stimulation in the subiculum we demonstrate a negative-going deflection followed by a positive-going deflection in the entorhinal cortex. This projection is capable of short-term plastic changes in the form of PPF. FIn addition, we demonstrate that long-term synaptic changes in the form of LTP and LTD could be sustained for at least 30min on this pathway. Finally we show that PPF changes after LTP and LTD, suggesting that a presynaptic mechanism may be involved in both of these pathways. [Copyright &y& Elsevier]

One niche of experimental biology that has experienced considerable progress is the neurobiology of learning and memory. A key contributor to such progress has been the widespread use of transgenic and 'knockout' mice to elucidate the mechanisms of identifiable phenotypes of learning and memory. Inbred mouse strains are needed to generate genetically modified mice. However, genetic variations between inbred strains can confound the interpretation of cellular neurophysiological phenotypes of mutant mice. It is known that altered physiological strength of synaptic transmission ('synaptic plasticity') can modify and regulate learning and memory. Characterization of the synaptic phenotypes of inbred mouse strains is needed to identify the most appropriate strains to use for generating mutant mouse models of memory function. More importantly, comparative electrophysiological analyses of inbred mice per se can also shed light on which forms of synaptic plasticity underlie particular types of learning and memory. Many such analyses have focused on synaptic plasticity in the hippocampus because of the critical roles of this brain structure in the formation and consolidation of long-term memories. Comparative electrophysiological data obtained from several inbred mouse strains are reviewed here to highlight the following key notions: (1) synaptic plasticity is influenced by the genetic backgrounds of inbred mice; (2) the plasticity of hippocampal synapses in inbred mice is `tuned' to particular temporal patterns of activity; (3) long-term potentiation, but not long-term depression, is a cellular correlate of behavioural memory performance in some strains; (4) synaptic phenotyping of inbred mouse strains can identify cellular models of memory impairment that can be used to elucidate mechanisms that may cause specific memory deficits. [ABSTRACT FROM AUTHOR]

Long-lasting neuroadaptations that occur during drug use and remain after withdrawal are thought to contribute to the persisting and compulsive nature of drug addiction and relapse. At the molecular and cellular levels, mechanisms that have been implicated in the normal process of memory formation are increasingly being identified as potential contributors to the persistence of the addicted state. To investigate the effect of cocaine self-administration on synaptic plasticity, rats were allowed to self-administer 0.5 mg/kg/infusion cocaine or 0.9% NaCl during 90 min sessions for 15 consecutive days. These cocaine and saline self-administration subjects were then restricted to their home cages for 3, 30, or 100 days (3, 30, and 100 day cocaine/saline withdrawal groups) before the assessment of the induction and reversal of long-term potentiation (LTP) in the CA1 region of hippocampal slices. The magnitude of LTP was increased in the 3-day cocaine withdrawal group as compared with the 3-day saline withdrawal group, but this effect was short lived, as the 30-day cocaine and saline withdrawal groups exhibited similar LTP magnitudes. Interestingly, LTP was significantly decreased in the 100-day cocaine withdrawal group compared with the 100-day saline withdrawal group. These results support the hypothesis that the capacity for LTP is persistently altered after withdrawal from exposure to an addictive substance. In addition, this alteration can be differentially expressed such that depending upon the duration of the withdrawal period following the last drug exposure, LTP may be enhanced, unchanged, or suppressed. [Copyright &y& Elsevier]

The relation between the acquisition of a skilled motor task and synaptic plasticity in the sensorimotor cortex of the awake, freely behaving rat was examined. Skilled-motor training was previously found to induce a functional reorganization of the caudal forelimb area, and to induce an increase in synaptic efficacy, measured in vitro, on the side contralateral to the reaching forelimb. Here, we repeatedly measured neocortical evoked potential recordings in awake, freely behaving rats to examine whether skilled training would induce changes in polysynaptic efficacy on the side contralateral to the reaching forelimb. We found that the increase in task proficiency, but not the acquisition of task requirements or the maintenance of task proficiency, induced an increase in synaptic efficacy on the side contralateral to the reaching forelimb. We also tested the hypothesis that skilled learning induced potentiation shares similar mechanisms to long-term potentiation (LTP) and long-term depression by artificially manipulating polysynaptic efficacy in skilled rats with high- and low-frequency stimulation. We observed that, compared with the ipsilateral side, less potentiation but more depression could be induced on the side contralateral to the reaching forelimb. We conclude that a transient, network-based LTP-like mechanism operates during the learning of a skilled motor task. [Copyright &y& Elsevier]

In this paper, we propose a complex neuro-memristive synapse that exhibits the physiological acts of synaptic potentiation and depression of the human-brain. Specifically, the proposed neuromorphic synapse efficiently imitates the synaptic plasticity, especially long-term potentiation (LTP) and depression (LTD), and short-term facilitation (STF) and depression (STD), phenomena of a biological synapse. Similar to biological synapse, the short- or long-term potentiation (STF and LTP) or depression (STD or LTD) of the memristive synapse are distinguished on the basis of time or repetition of input cycles. The proposed synapse is also designed to exhibit the effect of reuptake and neurotransmitters diffusion processes of a bio-synapse. In addition, it exhibits the distinct bio-realistic attributes, i.e., strong stimulation, exponentially decaying conductance trace of synapse, and voltage dependent synaptic responses, of a neuron. The neuro-memristive synapse is designed in SPICE and its bio-realistic functionalities are demonstrated via various simulations. [ABSTRACT FROM AUTHOR]