Changes In Synaptic Efficiency Research Articles

Acute Effects of Two Different Species of Amyloid-β on Oscillatory Activity and Synaptic Plasticity in the Commissural CA3-CA1 Circuit of the Hippocampus

Recent evidence indicates that soluble amyloid-β (Aβ) species induce imbalances in excitatory and inhibitory transmission, resulting in neural network functional impairment and cognitive deficits during early stages of Alzheimer's disease (AD). To evaluate the in vivo effects of two soluble Aβ species (Aβ25-35 and Aβ1-40) on commissural CA3-to-CA1 (cCA3-to-CA1) synaptic transmission and plasticity, and CA1 oscillatory activity, we used acute intrahippocampal microinjections in adult anaesthetized male Wistar rats. Soluble Aβ microinjection increased cCA3-to-CA1 synaptic variability without significant changes in synaptic efficiency. High-frequency CA3 stimulation was rendered inefficient by soluble Aβ intrahippocampal injection to induce long-term potentiation and to enhance synaptic variability in CA1, contrasting with what was observed in vehicle-injected subjects. Although soluble Aβ microinjection significantly increased the relative power of γ-band and ripple oscillations and significantly shifted the average vector of θ-to-γ phase-amplitude coupling (PAC) in CA1, it prevented θ-to-γ PAC shift induced by high-frequency CA3 stimulation, opposite to what was observed in vehicle-injected animals. These results provide further evidence that soluble Aβ species induce synaptic dysfunction causing abnormal synaptic variability, impaired long-term plasticity, and deviant oscillatory activity, leading to network activity derailment in the hippocampus.

Involvement of Pannexin-1 in the Mechanism of Deprivation Potentiation of Population Spikes of Neurons in Rat Hippocampal Field CA1

Testing of the connections of Schaffer collaterals with field CA1 neurons in living slices of rat hippocampus was used to study the mechanism of deprivation potentiation (DeP) of population spikes developing as a result of a 60-min pause in stimulation (deprivation). Previous studies have shown that DeP has the property of input specificity and the ability to persist for prolonged periods; it consists of two components with independent mechanisms of induction: an initial short-term “peak” of presynaptic origin and a long-lasting “plateau” with a Ca2+-dependent postsynaptic mechanism mediated by P2 purine receptors. Studies of the properties of the input specificity of DeP were run using stimulation of two different populations of Schaffer collaterals and recording of pop-spikes in the general population of neurons in field CA1. These experiments showed that changes in synaptic efficiency in the deprived input depend only on a presynaptic mechanism responsible for the development of the short-term component of DeP. Studies of the postsynaptic mechanism of induction of the long-term component of DeP demonstrated that the function of the adenosine triphosphate (ATP) source required for activation of P2 purine receptors is mediated by pannexin-1, which forms ATP-conducting channels on the postsynapse. A working model of the cyclic mechanism of induction of the long-term component of DeP is presented.

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

N-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related to schizophrenia, particularly in the hippocampus and the prefrontal cortex. It has been shown that prior long-term potentiation (LTP) occluded the increase of synaptic efficacy in the hippocampus-prefrontal cortex pathway induced by MK-801, a non-competitive NMDAr antagonist. However, it is not clear whether LTP could also modulate aberrant oscillations and short-term plasticity disruptions induced by NMDAr antagonists. Thus, we tested whether LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma cross-frequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in cortico-limbic circuits.

A proposed tandem mechanism for memory storage in neurons involving magnetite and prions

Knowledge about how information is stored in neurons of animals and in the human brain is still incomplete. A hypothesis related to long-term changes in synaptic efficiency has strong experimental support, but does not seem to be able to explain all observations. It has recently been proposed that magnetite together with a prion-like protein could be involved in a tandem mechanism for storage of memory in neurons in which electric impulses are received and reshaped by the magnetite to a form which can be accepted by the protein. The magnetite crystals can be magnetized by an electrical impulse, but they cannot hold the magnetism, which drops to zero after each impulse. Therefore, magnetite cannot be the substance in which information is stored. In the present paper we explain how a tandem mechanism could function in a neuron in which magnetite is situated together with a prion-like protein close to the cell surface membrane of the axon. We assume in addition that the information is stored in special storage neurons. With this, we propose a new hypothesis for information storage in neurons which could operate in addition to synaptic plasticity, but perhaps in different neurons.

Molecular Mechanism of Memory Modification

The present review of our own and published data proposes a hypothesis for the molecular mechanisms regulating synaptic efficiency which may underlie long-term changes in behavior and modification of memory on the reactivation. The hypotheses is based on data on role of the atypical protein kinase molecule Mζ in long-term changes in synaptic efficiency by controlling the delivery of AMPA receptors, and on data on the possible nitrosylation of these molecules by nitric oxide, which is produced in synapses when nerve cells are activated.

Transcranial direct current stimulation generates a transient increase of small-world in brain connectivity: an EEG graph theoretical analysis

Transcranial direct current stimulation (tDCS) is a non-invasive technique able to modulate cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. The aim of this study was to investigate-through graph theory analysis-how bipolar tDCS modulate cortical networks high-density EEG recordings were acquired before and after bipolar cathodal, anodal and sham tDCS involving the primary motor and pre-motor cortices of the dominant hemispherein 14 healthy subjects. Results showed that, after bipolar anodal tDCS stimulation, brain networks presented a less evident "small world" organization with a global tendency to be more random in its functional connections with respect to prestimulus condition in both hemispheres. Results suggest that tDCS globally modulates the cortical connectivity of the brain, modifying the underlying functional organization of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas. This study demonstrated that graph analysis approach to EEG recordings is able to intercept changes in cortical functions mediated by bipolar anodal tDCS mainly involving the dominant M1 and related motor areas. Concluding, tDCS could be an useful technique to help understanding brain rhythms and their topographic functional organization and specificity.

P110 Transcranial direct current stimulation of the brain motor area generates a transient increase of small worldnessy in connectivity: An EEG graph theoretical analysis

Introduction Transcranial direct current stimulation (tDCS) is a non-invasive method modulating cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. Objective In the present study we aimed to investigate the impact of bipolar tDCS on cortical networks connectivity through graph theoretical analysis. Materials & methods High-density EEG recordings were acquired before and after bipolar anodal, cathodal and sham tDCS applied over the primary motor cortex of the dominant hemisphere in 14 healthy subjects. Results Results showed that, after bipolar anodal tDCS stimulation over the dominant primary motor cortex the related brain network presented a more small-worldnessy, meaning a global tendency to be more random in its functional connections respect to prestimulus condition in both hemispheres. Conclusions Our results suggest that tDCS is able to modulate globally the cortical connectivity of the brain, modifying the underlying functional organization via complex pattern of direct and indirect cortical activations or inhibitions of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas.

Learning as a Functional State of the Brain: Studies in Wild-Type and Transgenic Animals.

Contemporary neuroscientists are paying increasing attention to subcellular, molecular, and electrophysiological mechanisms underlying learning and memory processes. Recent studies have examined the development of transgenic mice affected at different stages of the learning process, or have emulated in animals various human pathological conditions involving cognition and motor learning. However, a parallel effort is needed to develop stimulating and recording techniques suitable for use in behaving mice in order to understand activity-dependent synaptic changes taking place during the very moment of the learning process. The in vivo models should incorporate information collected from different molecular and in vitro approaches. Long-term potentiation (LTP) has been proposed as the neural mechanism underlying synaptic plasticity, and NMDA receptors have been proposed as the molecular substrate of LTP. It now seems necessary to study the relationship of both LTP and NMDA receptors to functional changes in synaptic efficiency taking place during actual learning in selected cerebral cortical structures. Here, we review data collected in our laboratory during the past 10years on the involvement of different hippocampal synapses in the acquisition of the classically conditioned eyelid responses in behaving mice. Overall the results indicate a specific contribution of each cortical synapse to the acquisition and storage of new motor and cognitive abilities. Available data show that LTP, evoked by high-frequency stimulation of Schaffer collaterals, disturbs both the acquisition of conditioned eyelid responses and the physiological changes that occur at hippocampal synapses during learning. Moreover, the administration of NMDA-receptor antagonists is able not only to prevent LTP induction in vivo, but also to hinder both the formation of conditioned eyelid responses and functional changes in the strength of the CA3-CA1 synapse. Nevertheless, many other neurotransmitter receptors, intracellular mediators, and transcription factors are also involved in learning and memory processes. In summary, it can be proposed that learning and memory in behaving mammals are the result of the activation of complex and distributed functional states involving many different cerebral cortical synapses, with the participation also of various neurotransmitter systems.

Spatial filter by spike timing dependent plasticity

Spike timing dependent plasticity (STDP) is found in various areas of the brain, visual cortex, hippocampus and hindbrain of electric fish, etc. The synaptic modification by STDP depends on time difference between presynaptic spike arrival and postsynaptic firing. If presynaptic neuron fires earlier than postsynaptic neuron dose, synaptic weight is strengthened. If postsynaptic neuron fires earlier than presynaptic neuron dose, synaptic weight is weakened. This learning rule is one example of various rules (hippocampal type). The learning rule of electric fish type is reversed. Changes of synaptic efficiency precisely depend on timing of pre- and postsynaptic spikes under STDP. Because of this precise dependence, STDP is thought to play the important role in temporal processing of stimuli. Temporal processing by STDP is well known. However, the role of STDP in spatial processing is not enough understood. To investigate spatial processing by STDP, We studied the role in spatial processing on interconnected network with STDP, using computer simulation. In this study, we found two type spatial filter by STDP on interconnected network. One is low pass filter using the learning rule of electric fish type. Another is edge-enhancing filter using the learning rule of hippocampus type. In this study, we calculated the response of interconnected neural network with STDP learning. The structure of the network is one-dimensional array. The neuron of the network has connection to neighbour neurons. In the case of learning rule of electric fish type, the network provided the function of low pass filter. The network was stimulated by direct current rectangularly distributed with noise. We examined two cases. In one case, synaptic modification did not occur (Fig ​(Fig1a).1a). In another case, synaptic modification occurred (Fig ​(Fig1b).1b). In the first case, Noise presented in response of the network and covered the rectangular form of stimulus. In the second case, noise was eliminated and the rectangular form of stimulus was represented. In the case of learning rule of hippocampal type, the network provided the function of edge-enhancing filter. The network was stimulated by direct current rectangularly distributed. The firing rate of the neuron that represents the edge of stimulus was larger than one of the others. This result shows that the network with hipocampal type STDP plays the role of edge-enhancing filter. These results show that interconnected network with STDP provides the function of spatial filter, and suggest that STDP would plays the important role in spatial processing. Figure 1 Response of network. Vertical and horizontal line indicates response of the network and neuronal number, respectively. (a) and (b) show the response of the network without and with STDP learning, respectively.

Metaplasticity Governs Natural Experience-Driven Plasticity of Nascent Embryonic Brain Circuits

During embryogenesis, brain neurons receiving the same sensory input may undergo potentiation or depression. While the origin of variable plasticity in vivo is unknown, it plays a key role in shaping dynamic neural circuit refinement. Here, we investigate effects of natural visual stimuli on neuronal firing within the intact, awake, developing brain using calcium imaging of 100 s of central neurons in the Xenopus retinotectal system. We find that specific patterns of visual stimuli shift population responses toward either potentiation or depression in an N-methyl-D-aspartate receptor (NMDA-R)-dependent manner. In agreement with Bienenstock-Cooper-Munro metaplasticity, our results show that functional potentiation or depression can be predicted by individual neurons' specific receptive field properties and historic firing rates. Interestingly, this activity-dependent metaplasticity is itself NMDA-R dependent. Furthermore, network analysis reveals increased correlated firing of neurons that undergo potentiation. These findings implicate metaplasticity as a natural property regulating experience-dependent refinement of nascent embryonic brain circuits.

Caloric Restriction Increases Learning Consolidation and Facilitates Synaptic Plasticity through Mechanisms Dependent on NR2B Subunits of the NMDA Receptor

One of the main focal points of aging research is the search for treatments that will prevent or ameliorate the learning and memory deficiencies associated with aging. Here we have examined the effects of maintaining mature mice on a long-term intermittent fasting diet (L-IFD). We found that L-IFD enhances learning and consolidation processes. We also assessed the long-term changes in synaptic efficiency in these animals. L-IFD mice showed an increase in low-theta-band oscillations, paired-pulse facilitation, and facilitation of long-term synaptic plasticity in the hippocampus with respect to mice fed ad libitum. In addition, we found an increase in the expression of the NMDA receptor subunit NR2B in some brain areas of L-IFD mice. Specific antagonism of this subunit in the hippocampus reversed the beneficial effects of L-IFD. These data provide a molecular and cellular mechanism by which L-IFD may enhance cognition, ameliorating some aging-associated cognitive deficits.

Cortical reorganization in the human brain

Does the human brain reorganize differently depending on the stimulus? Does the type of injury affect how the brain reacts, or does cortical reorganization follow a set pattern regardless of the etiology of injury? Past studies have focused on where cortical functions relocate to and what factors enhance or inhibit that relocation process. In this issue of Neurology , Burneo et al.1 and Pataraia et al.2 used magnetoencephalography (MEG) to compare how cortical reorganization differs in patients with different types of brain lesions. Until recently, the prevailing thought was that the brain’s ability to change is limited to the developing nervous system. It has now been firmly established that even the adult CNS is capable of developing adaptive changes and substantial cortical reorganization3 that may underlie recovery of function. Studies in both animals and humans have shown that damage to the CNS results in cortical reorganization that varies depending on age, extent and location of injury, and the presence of rehabilitative training. Plasticity, the ability of the CNS to adapt to new environmental requirements or lesions by functional changes in synapses, can occur at cortical and subcortical levels of the neuroaxis. The mechanisms implicated may include dendritic growth and synaptogenesis,4 changes in synaptic efficiency like long-term potentiation or depression, 5 and reorganizational changes in body part representations that are partially maintained by GABA.6 Cortical plasticity can …

The Kinetic Profile of Intracellular Calcium Predicts Long-Term Potentiation and Long-Term Depression

Efficiency of synaptic transmission within the neocortex is regulated throughout life by experience and activity. Periods of correlated or uncorrelated presynaptic and postsynaptic activity lead to enduring changes in synaptic efficiency [long-term potentiation (LTP) and long-term depression (LTD), respectively]. The initial plasticity triggering event is thought to be a precipitous rise in postsynaptic intracellular calcium, with higher levels inducing LTP and more moderate levels inducing LTD. We used a pairing protocol in visual cortical brain slices from young guinea pigs with whole-cell recording and calcium imaging to compare the kinetic profiles of calcium signals generated in response to individual pairings along with the cumulative calcium wave and plasticity outcome. The identical pairing protocol applied to layer 2/3 pyramidal neurons results in different plasticity outcomes between cells. These differences are not attributable to variations in the conditioning protocol, cellular properties, inter-animal variability, animal age, differences in spike timing between the synaptic response and spikes, washout of plasticity factors, recruitment of inhibition, or activation of different afferents. The different plasticity outcomes are reliably predicted by individual intracellular calcium transients in the dendrites after the first few pairings. In addition to the differences in the individual calcium transients, the cumulative calcium wave that spreads to the soma also has a different profile for cells that undergo LTP versus LTD. We conclude that there are biological differences between like-type cells in the dendritic calcium signals generated by coincident synaptic input and spiking that determine the sign of the plasticity response after brief associations.

LTP in cultured hippocampal–entorhinal cortex slices from young adult (P25-30) rats

Cultured hippocampal neurons and immature organotypic slice cultures overcome temporal limitations of acute hippocampal slices and have been useful for investigating long-lasting plasticity. Difficulties with culturing adult neurons have restricted such studies to preparations from embryonic, perinatal, and juvenile tissue. By improving the methods for culturing and maintaining hippocampal–entorhinal cortex slices obtained from mature rats (P25-30), we show that their use in long-term electrophysiological investigations is feasible. Our cultured slices maintained an intact and functional trisynaptic cascade, normal synaptic function, and reliable long-term recording stability for at least 14 days in vitro. The electrophysiological properties and, in particular, the induction of long-term potentiation (LTP) in our mature organotypic slices were highly sensitive to dissection and tissue culture techniques. We present data describing the extracellular stimulation requirements for LTP-induction and its long-lasting maintenance (>4 h) at the Schaffer-collateral-CA1 synapse, and show that such changes in synaptic efficiency are NMDA receptor dependent. Our hippocampal–entorhinal cortex cultures from mature tissue can retain the electrophysiological properties required for long-term plasticity for several weeks in vitro.

Cooperative changes in GABA, glutamate and activity levels: the missing link in cortical plasticity.

Different intracortical mechanisms have been reported to contribute to the substantial topographic reorganization of the mammalian primary visual cortex in response to matching lesions in the two retinas: an immediate expansion of receptive fields followed by a gradual shift of excitability into the deprived area and finally axonal sprouting of laterally projecting neurons months after the lesion. To gain insight into the molecular mechanisms of this adult plasticity, we used immunocytochemical and bioanalytical methods to measure the glutamate and GABA neurotransmitter levels in the visual cortex of adult cats with binocular central retinal lesions. Two to four weeks after the lesions, glutamate immunoreactivity was decreased in sensory-deprived cortex as confirmed by HPLC analysis of the glutamate concentration. Within three months normal glutamate immunoreactivity was restored. In addition, the edge of the unresponsive cortex was characterized by markedly increased glutamate immunoreactivity 2-12 weeks postlesion. This glutamate immunoreactivity peak moved into the deprived area over time. These glutamate changes corresponded to decreased spontaneous and visually driven activity in unresponsive cortex and to strikingly increased neuronal activity at the border of this cortical zone. Furthermore, the previously reported decrease in glutamic acid decarboxylase immunoreactivity was found to reflect decreased GABA levels in sensory-deprived cortex. Increased glutamate concentrations and neuronal activity, and decreased GABA concentrations, may be related to changes in synaptic efficiency and could represent a mechanism underlying the retinotopic reorganization that occurs well after the immediate receptive field expansion but long before the late axonal sprouting.

Reflex and muscular adaptations in rat soleus muscle after hindlimb suspension.

Reflex, mechanical and histochemical adaptations of the soleus muscle following 3 weeks of hindlimb suspension (HS) were measured in the rat. HS transformed the soleus muscle fibre type composition from predominantly slow, type I, to approximately equal proportions of fast, type II and slow fibres. Consistent with this transformation was an increase in the maximum shortening velocity, V(max), and a decrease in the stiffness of the series elastic component. Disuse also produced muscle atrophy and a resultant decrease in twitch and tetanic force. Reflex responses of the ankle extensors were also obtained at 5 and 9 weeks of age for six control rats (C group) and six rats subjected to HS for 3 weeks (HS group). The soleus reflexes to a mechanical tap applied to the Achilles tendon (T reflex) and to an electrical stimulation of the sciatic nerve (H reflex) were measured. The maximal amplitude of these reflexes (T(max) and H(max)) were normalised to the maximal direct motor response (M(max)) and the T(max)/H(max) ratio was also calculated to give an index of the relative adaptations of the peripheral and central components of the reflex pathway. The HS group showed significantly higher H reflex gains than the C group, possibly due to changes in synaptic efficiency after HS. Conversely, the HS group presented strongly inhibited T reflexes and negative gains for the T(max)/H(max) ratios. This result indicated a reduced spindle solicitation after HS, which may reflect changes in the spindle sensitivity itself, but it could also be due to the decrease in stiffness of the musculo-tendinous elements in series with the muscle spindles. Such mechanical changes may play an important part in the decreased T reflex responses.

Synaptic plasticity in the hippocampus during afferent activation reproducing the pattern of the theta rhythm (theta plasticity).

This review summarizes data on the plasticity of hippocampal synaptic pathways in conditions of afferent activation modeling the electrical activity of neurons during the theta rhythm. Activation with short trains of stimuli with frequencies of about 5 Hz efficiently induces long-term potentiation, i.e., stable facilitation of synaptic transmission. Contrarily, single stimuli presented at the same frequency "depotentiate" synapses or even induce long-term depression. Combined theta activity at two synaptic inputs, in phase with each other, induces long-term potentiation, while combined activity in antiphase produces long-term depression of the weakly-activated input (associative long-term potentiation and depression). Short trains of single stimuli at a frequency of 5 Hz induce heterosynaptic short-term depression: the efficiency of all synaptic inputs is decreased for time periods of the order of 1 min. Apart from changes in synaptic efficiency, theta activation affects the ability to induce synaptic rearrangements in conditions of subsequent afferent activation ("cryptic" plasticity). Thus, virtually all known types of synaptic plasticity are efficiently induced by afferent activation of the pattern of the hippocampal theta rhythm, which suggests the possible mechanisms for its roles in learning and memory processes.

The correlation between changes in synaptic efficiency and cellular excitability during the development of a conditioned reflex analog.

The calculation of the coefficient of correlation between changes in the direct (D) and monosynaptic (I) components of the pyramidal tract (PT) response made it possible to establish the presence of a positive linear association between conditioned reflex changes in synaptic efficiency and the shifts in cellular excitability observed at the same time. The coincidence of the maximal strength of this association with the greatest increase in cellular excitability which is dependent on the activation of motivatiogenic structures points to the role of these subcortical structures in the launching of intracellular reactions which leads to the formation of the overall molecular substrate which underlies interaction of membrane and synaptic mechanisms. The preceding of the greatest enhancement of synaptic efficiency by the maximal manifestation of the interaction attests to the contribution of this process to the manifestation of the principal mechanism of the conditioned reflex (CR).

The correlation between changes in synaptic efficiency and cellular excitability during the development of a conditioned reflex analog

The correlation between changes in synaptic efficiency and cellular excitability during the development of a conditioned reflex analog

Correlational association between changes in cell excitability and synaptic efficiency during posttetanic reorganizations in the cortex.

A positive linear association between the posttetanic changes in synaptic efficiency and the shifts in the cellular excitability observed at the same time was established using the method of calculation of the coefficient of correlation (CC) between the changes in the direct and synaptic components of the response of the pyramidal tract. The CC values found at the initial stages of the formation of the trace process decrease with time, and a significant correlational association between the changes in the components is absent by an hour after the tetanic stimulation. Such temporal specificity in the contingency of the mechanisms studied presupposes at a certain stage in the organization of the trace a communality of intracellular molecular substrate which determines the manifestation of these mechanisms. Correlation analysis carried out suggests that cortical plasticity is a complex dynamic system, the understanding of which requires not only the elucidation of the elementary cellular mechanisms forming it, but the study of the character of the interaction between them as well.