Efficiency Of Synaptic Transmission Research Articles

Неоднорідний розподіл і внесок P- та P/Q-типів кальцієвих каналів у короткочасну пластичність гальмівної синаптичної передачі між нейронами культури гіпокампа

In the present study, we investigated the sensitivity of GABAergic short-term plasticity to the selective P- and P/Q-type calcium channels blocker omega-agatoxin-IVA. To block the P-type channels we used 30 nM of this toxin and 200 nM of the toxin was used to block the P/Q channel types. The evoked inhibitory postsynaptic currents (eIPSC) were studied using patch-clamp technique in whole-cell configuration in postsynaptic neuron and local extracellular stimulation of single presynaptic axon by rectangular pulse. The present data show that the contribution of P- and P/Q-types channels to GABAergic synaptic transmission in cultured hippocampal neurons are 30% and 45%, respectively. It was shown that the mediate contribution of the P- and P/Q-types channels to the amplitudes of eIPSC is different to every discovered neuron. It means that distribution of these channels is non-uniform. To study the short-term plasticity of inhibitory synaptic transmission, axons of presynaptic neurons were paired-pulse stimulated with the interpulse interval of 150 ms. Neurons demonstrated both the depression and facilitation. The application of 30 nM and 200 nM of the blocker decreased the depression and increased facilitation to 8% and 11%, respectively. In addition, we found that the mediate contribution of the P- and P/Q-types channels to realization of synaptic transmission after the second stimuli is 4% less compared to that after the first one. Therefore, blocking of both P- and P/Q-types calcium channels can change the efficiency of synaptic transmission. In this instance it facilitates realization of the transmission via decreased depression or increased facilitation. These results confirm that the P- and P/Q-types calcium channels are involved in regulation of the short-term inhibitory synaptic plasticity in cultured hippocampal neurons.

Primary Afferent Depolarization and Frequency Processing in Auditory Afferents

Presynaptic inhibition is a widespread mechanism modulating the efficiency of synaptic transmission and in sensory pathways is coupled to primary afferent depolarizations. Axonal terminals of bush-cricket auditory afferents received 2-5 mV graded depolarizing inputs, which reduced the amplitude of invading spikes and indicated presynaptic inhibition. These inputs were linked to a picrotoxin-sensitive increase of Ca(2+) in the terminals. Electrophysiological recordings and optical imaging showed that in individual afferents the sound frequency tuning based on spike rates was different from the tuning of the graded primary afferent depolarizations. The auditory neuropil of the bush-cricket Mecopoda elongata is tonotopically organized, with low frequencies represented anteriorly and high frequencies represented posteriorly. In contrast graded depolarizing inputs were tuned to high-frequencies anteriorly and to low-frequencies posteriorly. Furthermore anterior and posterior axonal branches of individual afferents received different levels of primary afferent depolarization depending on sound frequency. The presence of primary afferent depolarization in the afferent terminals indicates that presynaptic inhibition may shape the synaptic transmission of frequency-specific activity to auditory interneurons.

Differential roles of GRIP1a and GRIP1b in AMPA receptor trafficking

Regulated trafficking controls AMPA receptor (AMPAR) number at the postsynaptic membrane to modify the efficiency of synaptic transmission. The PDZ proteins GRIP1 and the related ABP-L/GRIP2 bind AMPAR subunit GluA2, and have been proposed to play a role in AMPAR trafficking associated with Long Term Depression (LTD) of synaptic transmission. Both GRIP1 and ABP-L/GRIP2 exist in different splice isoforms, including alternative 18 amino acid domains at the extreme N-terminus, which determine whether the protein can be palmitoylated. The implications of this differential splicing for AMPAR trafficking is unknown. Here, we use surface biotinylation and quantitative Western blotting to show that the N-terminal splice variants GRIP1a and GRIP1b have differential effects in NMDA-induced AMPAR internalization in cultured hippocampal neurons. GRIP1a inhibits, but GRIP1b enhances this trafficking event. We further demonstrate that GRIP1a and GRIP1b have dramatically different subcellular distributions in cultured neurons and exhibit NMDA-dependent colocalisation with early endosomes. We propose that GRIP1 palmitoylation modulates NMDA-induced AMPAR internalisation by differential regulation of the early endosomal system.

Synaptic Inhibition in the Olfactory Bulb Accelerates Odor Discrimination in Mice

Local inhibitory circuits are thought to shape neuronal information processing in the central nervous system, but it remains unclear how specific properties of inhibitory neuronal interactions translate into behavioral performance. In the olfactory bulb, inhibition of mitral/tufted cells via granule cells may contribute to odor discrimination behavior by refining neuronal representations of odors. Here we show that selective deletion of the AMPA receptor subunit GluA2 in granule cells boosted synaptic Ca(2+) influx, increasing inhibition of mitral cells. On a behavioral level, discrimination of similar odor mixtures was accelerated while leaving learning and memory unaffected. In contrast, selective removal of NMDA receptors in granule cells slowed discrimination of similar odors. Our results demonstrate that inhibition of mitral cells controlled by granule cell glutamate receptors results in fast and accurate discrimination of similar odors. Thus, spatiotemporally defined molecular perturbations of olfactory bulb granule cells directly link stimulus similarity, neuronal processing time, and discrimination behavior to synaptic inhibition.

An Active Hardware Dendrite Model Capable of Inducing STDP

The brains of living organisms have excellent information-processing functions. Although various neuron models and artificial neural networks have been investigated, the information processing functions of biological neural networks have not yet been clarified. Recently, various research efforts have confirmed that dendrites perform an important role in brain information processing. Reportedly, STDP (Spike Timing Dependent synaptic Plasticity) is generated between inputs of pre-synaptic neurons and backpropagation of the active potential from dendrites of post-synaptic neuron, as revealed by physiological experiments. Using electronic circuits, we are constructing a hardware model with the characteristics of biological neurons.In this paper, we propose an active hardware dendrite model inducing STDP based on backpropagation phenomena of biological dendrites. Results clarified the following two points.1. The synaptic transmission efficiency of constructed model is changed by timing of the action potential of the input of pre-synaptic neuron and the action potential of backpropagation of the dendrite of the post-synaptic neuron.2. When Δt is small, the amplitude change becomes large. When Δt is large, the amplitude change becomes small

Paradoxical Sleep as a Tool for Understanding the Hippocampal Mechanisms of Contextual Memory

Existing data on the involvement of the hippocampus in contextual memory and the fact that contextual memory is impaired in dreams occurring during paradoxical sleep allowed us to suggest that one of the causes of this impairment consists of changes in the efficiency of synaptic transmission in the hippocampus due to increases (as compared with waking) in the concentrations of acetylcholine, dopamine, and cortisol, as well as the absence of serotonin and noradrenaline. Our previous analysis showed that in paradoxical sleep, long-term depression can be induced all components of the polysynaptic pathway through the hippocampal formation, while potentiation can occur at the inputs from the entorhinal cortex to hippocampal fields CA1 and CA3 and in the associative connections in field CA3. It is hypothesized that the correct functioning of episodic memory requires efficient transmission of signals in each component of the polysynaptic pathway through the hippocampus, allowing a neuronal representation of the context to be created within it. In the state of waking, reproduction of the context of an episode simultaneously activates the neuronal representation of the context remembered in the hippocampus and neuronal representations of the details of the episode remembered in those areas of the cortex in which they were processed. It follows from the proposed mechanism that any neurotransmitter or neuropeptide able to promote longterm potentiation in all components of the polysynaptic pathway through the hippocampus can improve episodic memory. As the consequences of the mechanism are consistent with experimental data, it can be used to seek agents improving episodic memory.

Changes in Neuropil Ultrastructure in Hippocampal Field CA1 in Rat Pups after Application of Hyaluronidase

Electron microscopy and electrophysiological studies were performed on cross-sectional slices of the hippocampus of four-week-old male rat pups (n = 35) to detect ultrastructural changes in hippocampal field CA1 and the characteristics of the formation of excitatory postsynaptic potentials in this area of the brain after incubation of slices in hyaluronidase solution (10 U/ml), whose specific substrate is the extracellular matrix glycosaminoglycan hyaluronic acid. At 1.5 min after enzyme application, there were reductions in synaptic cleft widths in axodendritic contacts of the striatum radiatum of hippocampal field CA1 by 15-25%, which were consistent with increases seen in the amplitudes of excitatory postsynaptic potentials. At 4.5 min of incubation, the lumens of synaptic clefts decreased by 45-55%: during this time there was blockade of signal transmission via Schäffer collaterals to hippocampal field CA1. Thus, the structural-functional state of glycosaminoglycans is among the factors determining the efficiency of synaptic transmission in the brain.

Cellular basis of temperature dependence of the food-procuring activity of the mollusc Lymnaea stagnalis

Neuronal correlates of temperature dependence of alimentary behavior were studied in experiments on molluscs. It was found that a decrease of temperature led to suppression of food-procuring activity of the animals: to a decrease of the consumed food amount and of the number of food holes on the substrate. These behavioral changes are associated with a fall of impulsation frequency of the motoneuron alimentary network and with decrease of efficiency of synaptic transmission within the limits of central generator of the Lymnaea stagnalis alimentary rhythm. It is suggested that change of character of intercellular interactions within the CNS limits underlies the temperature dependence of the mollusc food-procuring activity.

P.3.a.017 Decreased serum pro BDNF/BDNF ratio in patients with schizophrenia

Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (<12 μm) become depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75NTR prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an “out-of-sync, lose-your-link” fashion through proBDNF/p75NTR signaling to refine neuronal connectivity.

Spatial memory formation induces recruitment of NMDA receptor and PSD‐95 to synaptic lipid rafts

NMDA receptors (NMDARs) activation in the hippocampus and insular cortex is necessary for spatial memory formation. Recent studies suggest that localization of NMDARs to lipid rafts enhance their signalization, since the kinases that phosphorylate its subunits are present in larger proportion in lipid raft membrane microdomains. We sought to determine the possibility that NMDAR translocation to synaptic lipid rafts occurs during plasticity processes such as memory formation. Our results show that water maze training induces a rapid recruitment of NMDAR subunits (NR1, NR2A, NR2B) and PSD-95 to synaptic lipid rafts and decrease in the post-synaptic density plus an increase of NR2B phosphorylation at tyrosine 1472 in the rat insular cortex. In the hippocampus, spatial training induces selective translocation of NR1 and NR2A subunits to lipid rafts. These results suggest that NMDARs translocate from the soluble fraction of post-synaptic membrane (non-raft PSD) to synaptic lipid raft during spatial memory formation. The recruitment of NMDA receptors and other proteins to lipid rafts could be an important mechanism for increasing the efficiency of synaptic transmission during synaptic plasticity process.

The Interface between Extracellular and Transmembrane Domains of Homomeric Cys-Loop Receptors Governs Open-Channel Lifetime and Rate of Desensitization

The lifetimes of activated postsynaptic receptor channels contribute to the efficiency of synaptic transmission. Here we show that structural differences within the interface dividing extracellular and transmembrane domains of homomeric alpha7 and 5-HT(3A) receptors account for the large differences in open-channel lifetime and time of desensitization onset between these contrasting members of the Cys-loop receptor superfamily. For alpha7 receptors, agonist-evoked single-channel currents appear mainly as isolated brief openings (tau(o) = 0.35 ms), whereas macroscopic currents after a step pulse of agonist desensitize rapidly (tau(d) = 0.4 ms). In contrast for 5-HT(3A) receptors, agonist-evoked single-channel currents appear as clusters of many long openings in quick succession (tau(cluster) = 1.2 s), whereas macroscopic currents desensitize slowly (tau(d) = 1.1 s). A chimeric alpha7-5HT(3A) receptor exhibits functional properties intermediate between those of the parent receptors, but the functional signatures of each parent are reconstituted after substituting the major loops within the interface of the extracellular and transmembrane domains from the corresponding parent receptor. Furthermore, these structural loops contribute to open-channel lifetime and time of desensitization onset in a nonadditive manner. The results suggest that desensitization is the major determinant of the lifetimes of activated alpha7 and 5-HT(3A) receptors and that functional differences between the two receptors arise primarily through structural differences at the interface between extracellular and transmembrane domains.

Synaptic Metaplasticity through NMDA Receptor Lateral Diffusion

Lateral diffusion of glutamate receptors was proposed as a mechanism for regulating receptor numbers at synapses and affecting synaptic functions, especially the efficiency of synaptic transmission. However, a direct link between receptor lateral diffusion and change in synaptic function has not yet been established. In the present study, we demonstrated NMDA receptor (NMDAR) lateral diffusion in CA1 neurons in hippocampal slices by detecting considerable recovery of spontaneous or evoked EPSCs from the block of (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], an irreversible NMDAR open-channel blocker. We observed changes on both the number and the composition of synaptic NMDAR on recovery. More importantly, after the recovery, long-term potentiation (LTP)-producing protocol induced only LTD (long-term depression) instead of LTP. In contrast, a complete recovery from competitive NMDAR blocker D,L-AP-5 was observed without subsequent changes on synaptic plasticity. Our data suggest a revised model of NMDAR trafficking wherein extrasynaptic NMDARs, mostly NR1/NR2B receptors, move laterally into synaptic sites, resulting in altered rule of synaptic modification. Thus, CA1 synapses exhibit a novel form of metaplasticity in which the direction of synaptic modification can be reverted through subtype-specific lateral diffusion of NMDA receptors.

The contribution of synaptic plasticity in the basal ganglia to the processing of visual information

A mechanism for the involvement of the basal ganglia in the processing of visual information, based on dopamine-dependent modulation of the efficiency of synaptic transmission in interconnected parallel associative and limbic cortex-basal ganglia-thalamus-cortex circuits, is proposed. Each circuit consists of a visual or prefrontal area of the cortex connected with the thalamic nucleus and the corresponding areas in different nuclei of the basal ganglia. The circulation of activity in these circuits is supported by the recurrent arrival of information in the thalamus and cortex. Dopamine released in response to a visual stimulus modulates the efficiencies of "strong" and "weak" corticostriatal inputs in different directions, and the subsequent reorganization of activity in the circuit leads to disinhibition (inhibition) of the activity of those cortical neurons which are "strongly" ("weakly") excited by the visual stimulus simultaneously with dopaminergic cells. The pattern in each cortical area is the neuronal reflection of the properties of the visual stimulus processed by this area. Excitation of dopaminergic cells by the visual stimulus via the superior colliculi requires parallel activation of the disinhibitory input to the superior colliculi via the thalamus and the "direct" pathway" in the basal ganglia. The prefrontal cortex, excited by the visual stimulus via the mediodorsal nucleus of the thalamus, mediates the descending influence on the activity of dopaminergic cells, simultaneously controlling dopamine release in different areas of the striatum and thus facilitating the mutual selection of neural reflections of the individual properties of the visual stimulus and their binding into an integral image.

Molecular Mechanism of Learning and Memory Based on the Research for Ca&lt;sup&gt;2+&lt;/sup&gt;/Calmodulin-dependent Protein Kinase II

In the central nervous system (CNS), the synapse is a specialized junctional complex by which axons and dendrites emerging from different neuron intercommunicates. Changes in the efficiency of synaptic transmission are important for a number of aspects of neural function. Much has been learned about the activity-dependent synaptic modifications that are thought to underlie memory storage, but the mechanism by which these modifications are stored remains unclear. Thus, it is important to find and characterize "memory molecules," and "memory apparatus or memory forming apparatus." A good candidate for the storage mechanism is Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II). CaM kinase II is one of the most prominent protein kinases, present in essentially every tissue but most concentrated in the brain. Neuronal CaM kinase II regulates important neuronal functions, including neurotransmitter synthesis, neurotransmitter release, modulation of ion channel activity, cellular transport, cell morphology and neurite extension, synaptic plasticity, learning and memory, and gene expression. Studies concerning this kinase open a door of the molecular basis of nerve function, especially learning and memory, and indicate one direction for the studies in the field of neuroscience. This review presents molecular structure, properties and functions of CaM kinase II, as a major component of neuron, which are mainly developed in our laboratory.

What are the mechanisms underlying the involvement of different subtypes of NMDA receptors in inducing long-term potentiation and depression in the hippocampus?

It has been hypothesized that the sign (direction) of modification of the efficiency of synaptic transmission depends on the subtype of N-methyl-D-aspartate (NMDA)-sensitive receptors involved. Activation of NMDA receptors with 2A subunits facilitates the induction of long-term potentiation, while receptors with 2B subunits facilitate the induction of long-term depression. However, experimental data have been obtained which contradict this hypothesis. We suggest an alternative hypothesis to explain currently available data. According to this hypothesis, activation of NMDA receptors containing different subunits can lead both to long-term potentiation and long-term depression, depending on the post-tetanic increase in the postsynaptic Ca(2+) concentration relative to the increase induced by preceding stimulation. Activation of NMDA receptors containing 2B subunits can lead to long-term depression of the excitatory input to pyramidal neurons because of the presence of these receptors on inhibitory interneurons, with induction of long-term potentiation on the interneuron and potentiation of inhibitory transmission between interneurons and pyramidal cells.

Perceptual Training of Phoneme Identification for Hearing Loss

Synaptic connections in the auditory system change throughout life in response to the changing acoustic environment. These changes help to compensate for sensorineural hearing loss (SNHL) and the consequent impairment of high-frequency hearing by enhancing the efficiency of synaptic transmission of low-frequency signals. They also help to compensate for the inevitable deterioration in the central auditory system that occurs with normal aging even without clinically significant hearing loss. However, in many cases the neuroplastic changes are insufficient to maintain optimal speech comprehension. Indeed, the enhanced transmission of low-frequency phonetic cues that occurs with longstanding SNHL may interfere with a patient's ability to use the high-frequency phonetic cues that are restored by hearing aids. Adaptive perceptual training using tasks that require high-frequency phonetic cue processing can drive neuroplastic change in auditory cortex to improve speech discrimination. The authors tested the benefits of at-home personal computer-based phoneme identification training in new hearing aid (HA) users and found that it produced significant benefit in phoneme identification by reducing phonetic confusions and enhancing the patient's abilities to identify previously difficult syllables. Perceptual training is a promising and cost-effective tool for enhancing speech perception in HA users who have difficulty in understanding everyday speech.

Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF‐heterozygous mice

The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival, axonal and dendritic growth and synapse formation. BDNF has also been reported to mediate visual cortex plasticity. Here we studied the cellular mechanisms of BDNF-mediated changes in synaptic plasticity, excitatory synaptic transmission and long-term potentiation (LTP) in the visual cortex of heterozygous BDNF-knockout mice (BDNF(+/-)). Patch-clamp recordings in slices showed an approximately 50% reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) compared to wild-type animals, in the absence of changes in mEPSC amplitudes. A presynaptic impairment of excitatory synapses from BDNF(+/-) mice was further indicated by decreased paired-pulse ratio and faster synaptic fatigue upon prolonged repetitive stimulation at 40 Hz. In accordance, presynaptic theta-burst stimulation (TBS) failed to induce LTP at layer IV to layers II-III synapses during extracellular field-potential recordings in BDNF(+/-) animals. Changes in postsynaptic function could not be detected, as no changes were observed in either the amplitudes of evoked EPSCs, the ratios of AMPA : NMDA currents or the kinetics of evoked AMPA and NMDA EPSCs. In line with this observation, an LTP pairing paradigm that relies on direct postsynaptic depolarization under patch-clamp conditions could be induced successfully in BDNF(+/-) animals. These data suggest that a chronic reduction in the expression of BDNF to nearly 50% attenuates the efficiency of presynaptic glutamate release in response to repetitive stimulation, thereby impairing presynaptically evoked LTP in the visual cortex.

Learning and memory: Traditional and systems approaches

The aims of the present work were to consider the characteristics of learning and memory from the point of view of a systems approach and to compare this view with the traditional approach. Neuron activity is regarded not as a response to the synaptic influx resulting in excitation but as a means of altering the cell's relationship with its environment, whose "action" is to eliminate discordance between the cell's "needs" and its microenvironment. The neuronal mechanisms of learning and consolidation of memory are regarded not as formation of a stable increase in the efficiency of synaptic transmission in circuits of connected neurons, but as a system genesis event which confers new system specializations on neurons which do not have to be directly connected synaptically. The roles of the processes of selection, reconsolidatory modification of previously formed memories, gene activation, neurogenesis, and apoptosis in systems genesis occurring both in normal and pathological conditions are discussed. Individual development is regarded as a sequence of system genesis events. The systems approach is applied to the phenomenon of long-term potentiation. In conclusion, a scheme including different types and stages of memory formation is presented.

Efficiency of Synaptic Transmission of Single-Photon Events from Rod Photoreceptor to Rod Bipolar Dendrite

A rod transmits absorption of a single photon by what appears to be a small reduction in the small number of quanta of neurotransmitter ( Q count) that it releases within the integration period (∼0.1 s) of a rod bipolar dendrite. Due to the quantal and stochastic nature of release, discrete distributions of Q count for darkness versus one isomerization of rhodopsin (R*) overlap. We suggested that release must be regular to narrow these distributions, reduce overlap, reduce the rate of false positives, and increase transmission efficiency (the fraction of R* events that are identified as light). Unsurprisingly, higher quantal release rates ( Q rates) yield higher efficiencies. Focusing here on the effect of small changes in Q rate, we find that a slightly higher Q rate yields greatly reduced efficiency, due to a necessarily fixed quantal-count threshold. To stabilize efficiency in the face of drift in Q rate, the dendrite needs to regulate the biochemical realization of its quantal-count threshold with respect to its Q count. These considerations reveal the mathematical role of calcium-based negative feedback and suggest a helpful role for spontaneous R*. In addition, to stabilize efficiency in the face of drift in degree of regularity, efficiency should be ≈50%, similar to measurements.

Ultrastructural features of hippocampal CA1 synapses with respect to synaptic enhancement following repeated PKA activation

We reported previously that repeated activations, but not a single activation, of cyclic AMP-dependent protein kinase (PKA), led to a slowly developing (requiring ∼1 week to develop) long-lasting (lasting ≥3 weeks) enhancement of synaptic transmission efficiency in the organotypic slice culture of the rat hippocampus. It was accompanied by an increase in the number of synapses identified immunohistochemically. To answer the question of whether the “perforated synapse”, which is known to occur transiently after the induction of long-term potentiation (LTP) in combination with the enlargement of postsynaptic density (PSD), is involved also in this slow/persistent synaptic enhancement, we examined the ultrastructural changes after the repeated activations of PKA. The answer was partially yes (occurrence of perforated synapses was increased) but partially no (the increase in the number of perforated synapses was not transient but persistent; mean apparent size of PSD did not increase). These results suggest that the mechanism of the slow/persistent synaptogenesis shares limited features with the mechanism of the quick/transient morphogenesis after LTP.