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A brief tetanic stimulation has a very different effect on the subsequent isometric twitch force of fast and slow skeletal muscles. Fast muscle responds with an enhanced twitch force which doubles that of the pre-tetanic value, whereas slow muscle depresses the post-tetanic twitch by about 20%. Twitch potentiation of fast muscle has long been known to be due to myosin light chain 2 phosphorylation. It is proposed that post-tetanic twitch depression in slow muscle is due to the dephosphorylation of the slow isoform of the thick filament protein, myosin-binding protein-C, by Ca2+/calmodulin-activated phosphatase calcineurin, whilst its phosphorylation underlies the force enhancement due to β-adrenergic stimulation in slow and fast muscle. [ABSTRACT FROM AUTHOR]

Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3-to-CA1 synapse and the granule cell parallel fiber (PF)-to-Purkinje cell (PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. In Munc18-1SA mice, 70% of PTP remained at CA3-to-CA1 synapses, and the amplitude of PTP was not reduced at PF-to-PC synapses. These findings indicate that at both CA3-to-CA1 and PF-to-PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1.SIGNIFICANCE STATEMENT A leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C (PKC) phosphorylation of Munc18-1. This study tests this mechanism by creating a knock-in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3-to-CA1 synapses or at cerebellar granule cell-to-Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

The main advantages of spiking neural networks are the high biological plausibility and their fast response due to spiking behaviour. The response time decreases significantly in the hardware implementation of SNN because the neurons operate in parallel. Compared with the traditional computational neural network, the SNN use a lower number of neurons, which also reduces their cost. Another critical characteristic of SNN is their ability to learn by event association that is determined mainly by postsynaptic mechanisms such as long-term potentiation. However, in some conditions, presynaptic plasticity determined by post-tetanic potentiation occurs due to the fast activation of presynaptic neurons. This violates the Hebbian learning rules that are specific to postsynaptic plasticity. Hebbian learning improves the SNN ability to discriminate the neural paths trained by the temporal association of events, which is the key element of learning in the brain. This paper quantifies the efficiency of Hebbian learning as the ratio between the LTP and PTP effects on the synaptic weights. On the basis of this new idea, this work evaluates for the first time the influence of the number of neurons on the PTP/LTP ratio and consequently on the Hebbian learning efficiency. The evaluation was performed by simulating a neuron model that was successfully tested in control applications. The results show that the firing rate of postsynaptic neurons p o s t depends on the number of presynaptic neurons p r e , which increases the effect of LTP on the synaptic potentiation. When p o s t activates at a requested rate, the learning efficiency varies in the opposite direction with the number of p r e s , reaching its maximum when fewer than two p r e s are used. In addition, Hebbian learning is more efficient at lower presynaptic firing rates that are divisors of the target frequency of p o s t . This study concluded that, when the electronic neurons additionally model presynaptic plasticity to LTP, the efficiency of Hebbian learning is higher when fewer neurons are used. This result strengthens the observations of our previous research where the SNN with a reduced number of neurons could successfully learn to control the motion of robotic fingers. [ABSTRACT FROM AUTHOR]

The vertebrates' scaffold proteins of the Dlg-MAGUK family are involved in the recruitment, clustering, and anchoring of glutamate receptors to the postsynaptic density, particularly the NMDA subtype glutamate-receptors (NRs), necessary for long-term memory and LTP. In Drosophila, the only gene of the subfamily generates two main products, dlgA, broadly expressed, and dlgS97, restricted to the nervous system. In the Drosophila brain, NRs are expressed in the adult brain and are involved in memory, however, the role of Dlg in these processes and its relationship with NRs has been scarcely explored. Here, we show that the dlg mutants display defects in short-term memory in the olfactory associative-learning paradigm. These defects are dependent on the presence of DlgS97 in the Mushroom Body (MB) synapses. Moreover, Dlg is immunoprecipitated with NRs in the adult brain. Dlg is also expressed in the larval neuromuscular junction (NMJ) pre and post-synaptically and is important for development and synaptic function, however, NR is absent in this synapse. Despite that, we found changes in the short-term plasticity paradigms in dlg mutant larval NMJ. Together our results show that larval NMJ and the adult brain relies on Dlg for short-term memory/plasticity, but the mechanisms differ in the two types of synapses. [ABSTRACT FROM AUTHOR]

UnlabelledPost-tetanic potentiation (PTP) is a widespread form of short-term synaptic plasticity in which a period of elevated presynaptic activation leads to synaptic enhancement that lasts tens of seconds to minutes. A leading hypothesis for the mechanism of PTP is that tetanic stimulation elevates presynaptic calcium that in turn activates calcium-dependent protein kinase C (PKC) isoforms to phosphorylate targets and enhance neurotransmitter release. Previous pharmacological studies have implicated this mechanism in PTP at hippocampal synapses, but the results are controversial. Here we combine genetic and pharmacological approaches to determine the role of classic PKC isoforms in PTP. We find that PTP is unchanged in PKC triple knock-out (TKO) mice in which all calcium-dependent PKC isoforms have been eliminated (PKCα, PKCβ, and PKCγ). We confirm previous studies and find that in wild-type mice 10 μm of the PKC inhibitor GF109203 eliminates PTP and the PKC activator PDBu enhances neurotransmitter release and occludes PTP. However, we find that the same concentrations of GF109203 and PDBu have similar effects in TKO animals. We also show that 2 μm GF109203 does not abolish PTP even though it inhibits the PDBu-dependent phosphorylation of PKC substrates. We conclude that at the CA3 to CA1 synapse Ca(2+)-dependent PKC isoforms do not serve as calcium sensors to mediate PTP.Significance statementNeurons dynamically regulate neurotransmitter release through many processes known collectively as synaptic plasticity. Post-tetanic potentiation (PTP) is a widespread form of synaptic plasticity that lasts for tens of seconds that may have important computational roles and contribute to short-term memory. According to a leading mechanism, presynaptic calcium activates protein kinase C (PKC) to increase neurotransmitter release. Pharmacological studies have also implicated this mechanism at hippocampal CA3 to CA1 synapses, but there are concerns about the specificity of PKC activators and inhibitors. We therefore used a molecular genetic approach and found that PTP was unaffected when all calcium-dependent PKC isozymes were eliminated. We conclude that PKC isozymes are not the calcium sensors that mediate PTP at the CA3 to CA1 synapse.

The main advantages of spiking neural networks are the high biological plausibility and their fast response due to spiking behaviour. The response time decreases significantly in the hardware implementation of SNN because the neurons operate in parallel. Compared with the traditional computational neural network, the SNN use a lower number of neurons, which also reduces their cost. Another critical characteristic of SNN is their ability to learn by event association that is determined mainly by postsynaptic mechanisms such as long-term potentiation. However, in some conditions, presynaptic plasticity determined by post-tetanic potentiation occurs due to the fast activation of presynaptic neurons. This violates the Hebbian learning rules that are specific to postsynaptic plasticity. Hebbian learning improves the SNN ability to discriminate the neural paths trained by the temporal association of events, which is the key element of learning in the brain. This paper quantifies the efficiency of Hebbian learning as the ratio between the LTP and PTP effects on the synaptic weights. On the basis of this new idea, this work evaluates for the first time the influence of the number of neurons on the PTP/LTP ratio and consequently on the Hebbian learning efficiency. The evaluation was performed by simulating a neuron model that was successfully tested in control applications. The results show that the firing rate of postsynaptic neurons post depends on the number of presynaptic neurons pre, which increases the effect of LTP on the synaptic potentiation. When post activates at a requested rate, the learning efficiency varies in the opposite direction with the number of pres, reaching its maximum when fewer than two pres are used. In addition, Hebbian learning is more efficient at lower presynaptic firing rates that are divisors of the target frequency of post. This study concluded that, when the electronic neurons additionally model presynaptic plasticity to LTP, the efficiency of Hebbian learning is higher when fewer neurons are used. This result strengthens the observations of our previous research where the SNN with a reduced number of neurons could successfully learn to control the motion of robotic fingers.

Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3-to-CA1 synapse and the granule cell parallel fiber (PF)-to-Purkinje cell (PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. In Munc18-1SA mice, 70% of PTP remained at CA3-to-CA1 synapses, and the amplitude of PTP was not reduced at PF-to-PC synapses. These findings indicate that at both CA3-to-CA1 and PF-to-PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1. [ABSTRACT FROM AUTHOR]

In presynaptic boutons, calcium (Ca(2+)) triggers both neurotransmitter release and short-term synaptic plasticity. Whereas synaptotagmins are known to mediate vesicle fusion through binding of high local Ca(2+) to their C2 domains, the proteins that sense smaller global Ca(2+) increases to produce short-term plasticity have remained elusive. Here, we identify a Ca(2+) sensor for post-tetanic potentiation (PTP), a form of plasticity thought to underlie short-term memory. We find that at the functionally mature calyx of Held synapse the Ca(2+)-dependent protein kinase C isoforms α and β are necessary for PTP, and the expression of PKCβ in PKCαβ double knockout mice rescues PTP. Disruption of Ca(2+) binding to the PKCβ C2 domain specifically prevents PTP without impairing other PKCβ-dependent forms of synaptic enhancement. We conclude that different C2-domain-containing presynaptic proteins are engaged by different Ca(2+) signals, and that Ca(2+) increases evoked by tetanic stimulation are sensed by PKCβ to produce PTP.DOI: http://dx.doi.org/10.7554/eLife.03011.001.

The complex manner in which patterns of presynaptic neural activity are translated into short-term plasticity (STP) suggests the existence of multiple presynaptic calcium (Ca(2+)) sensors, which regulate the amplitude and time-course of STP and are the focus of this review. We describe two canonical Ca(2+)-binding protein domains (C2 domains and EF-hands) and define criteria that need to be met for a protein to qualify as a Ca(2+) sensor mediating STP. With these criteria in mind, we discuss various forms of STP and identify established and putative Ca(2+) sensors. We find that despite the multitude of proposed sensors, only three are well established in STP: Munc13, protein kinase C (PKC) and synaptotagmin-7. For putative sensors, we pinpoint open questions and potential pitfalls. Finally, we discuss how the molecular properties and modes of action of Ca(2+) sensors can explain their differential involvement in STP and shape net synaptic output.

We used genetic and pharmacological approaches to identify the signaling pathways involved in augmentation and potentiation, two forms of activity dependent, short-term synaptic plasticity that enhance neurotransmitter release. Trains of presynaptic action potentials produced a robust increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs). Following the end of the stimulus, mEPSC frequency followed a bi-exponential decay back to basal levels. The time constants of decay identified these two exponential components as the decay of augmentation and potentiation, respectively. Augmentation increased mEPSC frequency by 9.3-fold, while potentiation increased mEPSC frequency by 2.4-fold. In synapsin triple-knockout (TKO) neurons, augmentation was reduced by 83% and potentiation was reduced by 74%, suggesting that synapsins are key signaling elements in both forms of plasticity. To examine the synapsin isoforms involved, we expressed individual synapsin isoforms in TKO neurons. While synapsin IIIa rescued both augmentation and potentiation, none of the other synapsin isoforms produced statistically significant amounts of rescue. To determine the involvement of protein kinases in these two forms of short-term plasticity, we examined the effects of inhibitors of protein kinases A (PKA) and C (PKC). While inhibition of PKC had little effect, PKA inhibition reduced augmentation by 76% and potentiation by 60%. Further, elevation of intracellular cAMP concentration, by either forskolin or IBMX, greatly increased mEPSC frequency and occluded the amount of augmentation and potentiation evoked by electrical stimulation. Finally, mutating a PKA phosphorylation site to non-phosphorylatable alanine largely abolished the ability of synapsin IIIa to rescue both augmentation and potentiation. Together, these results indicate that PKA activation is required for both augmentation and potentiation of spontaneous neurotransmitter release and that PKA-mediated phosphorylation of synapsin IIIa underlies both forms of presynaptic short-term plasticity.

We have demonstrated the co-existence of reliable analog and digital switching characteristics with tantalum oxide based memristor by appropriate rapid thermal annealing (RTA). The device without RTA exhibits a digital SET and multilevel RESET for positive and negative sweeps, respectively. On the other hands, the device shows only analog switching characteristics such that current level increases and decreases gradually for successive positive and negative voltage sweeps, respectively, before any electroforming process with the RTA in the nitrogen ambient at the crystalline temperature of tantalum oxide which is 700 °C for 60 s. Once electroforming process is done, the device exhibits a reliable digital switching with SET at positive sweep and RESET at negative sweep voltages. In the analog state of the device we successfully emulate the synaptic characteristic of the device like spike-rate dependent plasticity (SRDP), pulse-paired facilitation (PPF) and post-tetanic potentiation (PTP). Finally, the Hermann Ebbinghaus forgetting curve is obtained from these devices. The conversion of the device from the digital SET and multilevel RESET to analogue switching is attributed to structural transition of amorphous tantalum oxide to polycrystalline tantalum oxide, different defect density and interface variation in the device. [ABSTRACT FROM AUTHOR]

The presynaptic mechanism of short-term plasticity of synaptic transmission was studied by analyzing the effects of rhythmic orthodromic stimulation of the intestinal nerve, inducing short-term potentiation of evoked EPSP, on spontaneous EPSP in defensive behavior command neurons in the common snail. Rhythmic stimulation had no effect on the amplitude of spontaneous EPSP but led to significant increases in the number of spontaneous EPSP. The increase in the frequency of spontaneous EPSP suggested a role for a presynaptic mechanism in the short-term potentiation of synaptic transmission. This presynaptic mechanism may include a decrease in the action potential generation threshold (AP) in presynaptic neurons, which leads to an increase in the proportion of spontaneously active neurons and, thus, supports an increase in the number of spontaneous presynaptic AP. [ABSTRACT FROM AUTHOR]

Background Inbred mouse strains are differentially sensitive to the acute effects of ethanol (EtOH) and are useful tools for examining how unique genomes differentially affect alcohol-related behaviors and physiology. DBA/2J mice have been shown to be sensitive to the acute anxiolytic effects of alcohol as well as the anxiogenic effects of withdrawal from chronic alcohol exposure, while B6 mice are resistant to both. Considering that the basolateral amygdala (BLA) is an important brain region for the acute and chronic effects of EtOH on fear and anxiety related behaviors, we hypothesized that there would be strain-dependent differences in the acute effects of EtOH in BLA slices. Methods We utilized patch clamp electrophysiology in BLA coronal slices from 4 inbred mouse strains (A/J, BALBcJ, C57 BL/6J, and DBA/2J) to examine how genetic background influences acute EtOH effects on synaptic vesicle recycling and post-tetanic potentiation (PTP) in response to low (2 Hz)- and high (40 Hz)-frequency stimulation. Results We found that EtOH inhibited synaptic vesicle recycling in a strain- and stimulation frequency-dependent manner. Vesicle recycling in DBA/2J and BALBcJ cells was inhibited by acute EtOH during both low- and high-frequency stimulation, while recycling measured from A/J cells was sensitive only during high-frequency stimulation. Recycling at C57 BL/6J synapses was insensitive to EtOH regardless of stimulation frequency. We additionally found that cells from DBA/2J and BALBcJ mice were sensitive to EtOH-mediated inhibition of PTP. Conclusions Acute EtOH application inhibited vesicle recycling and PTP at glutamatergic synapses in both a strain- and frequency-dependent fashion. Several presynaptic proteins that contribute to synaptic vesicle priming in addition to PTP have been implicated in alcohol-related behaviors, including Munc13, Munc18, and RIM proteins, making them potential candidates for the molecular mechanism controlling these effects. [ABSTRACT FROM AUTHOR]

Post-tetanic potentiation (PTP) is a widespread form of short-term synaptic plasticity in which a period of elevated presynaptic activation leads to synaptic enhancement that lasts tens of seconds to minutes. A leading hypothesis for the mechanism of PTP is that tetanic stimulation elevates presynaptic calcium that in turn activates calcium-dependent protein kinase C (PKC) isoforms to phosphorylate targets and enhance neurotransmitter release. Previous pharmacological studies have implicated this mechanism in PTP at hippocampal synapses, but the results are controversial. Here we combine genetic and pharmacological approaches to determine the role of classic PKC isoforms in PTP. We find that PTP is unchanged in PKC triple knock-out (TKO) mice in which all calcium-dependent PKC isoforms have been eliminated (PKCα, PKCβ, and PKCγ). We confirm previous studies and find that in wild-type mice 10 µM of the PKC inhibitor GF109203 eliminates PTP and the PKC activator PDBu enhances neurotransmitter release and occludes PTP. However, we find that the same concentrations of GF109203 and PDBu have similar effects in TKO animals. We also show that 2 µM GF109203 does not abolish PTP even though it inhibits the PDBu-dependent phosphorylation of PKC substrates. We conclude that at the CA3 to CA1 synapse Ca2+- dependent PKC isoforms do not serve as calcium sensors to mediate PTP. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to evaluate post-tetanic potentiation of muscle twitch in myasthenia gravis (MG). Methods Post-tetanic potentiation was evaluated by recording the compound muscle action potential (CMAP) of abductor pollicis brevis and movement-related potential (MRP) of the thumb using an accelerometer after tetanic stimulation of the median nerve at the wrist. After baseline recording, tetanic stimulation was delivered to the median nerve at a frequency of 10 Hz for 10 s. The CMAP and MRP were successively recorded at baseline and at 5, 10, 30, 60, 90 and 120 s after tetanic stimulation. The chronological changes of CMAPs and MRPs were recorded bilaterally in 11 patients with MG, 9 patients with myopathies (disease controls), and 25 healthy control subjects. Results Maximal acceleration of MRP was significantly elevated during 10 s after tetanic stimulation without any CMAP changes in all groups. However, statistical analysis detected a significant decrease in post-tetanic potentiation of maximal acceleration of MRP in MG patients only compared to healthy controls, but not in myopathy patients, which may imply impairment of excitation–contraction coupling in MG. Conclusions Post-tetanic potentiation of muscle twitch is significantly diminished in MG, suggesting impaired excitation–contraction coupling. Significance Measurement of post-tetanic potentiation using an accelerometer is a simple and sensitive method to detect impairment of excitation–contraction coupling in MG. [ABSTRACT FROM AUTHOR]

In presynaptic boutons, calcium (Ca2+) triggers both neurotransmitter release and short-term synaptic plasticity. Whereas synaptotagmins are known to mediate vesicle fusion through binding of high local Ca2+ to their C2 domains, the proteins that sense smaller global Ca2+ increases to produce short-term plasticity have remained elusive. Here, we identify a Ca2+ sensor for post-tetanic potentiation (PTP), a form of plasticity thought to underlie short-term memory. We find that at the functionally mature calyx of Held synapse the Ca2+-dependent protein kinase C isoforms α and β are necessary for PTP, and the expression of PKCβ in PKCαβ double knockout mice rescues PTP. Disruption of Ca2+ binding to the PKCβ C2 domain specifically prevents PTP without impairing other PKCβ-dependent forms of synaptic enhancement. We conclude that different C2-domain-containing presynaptic proteins are engaged by different Ca2+ signals, and that Ca2+ increases evoked by tetanic stimulation are sensed by PKCβ to produce PTP.

Interventions for strengthening intrinsic foot muscles may be beneficial for rehabilitation from overuse injuries. In this study the acute effects of high-frequency, low-intensity wide-pulse electrical stimulation (WPS) over an intrinsic muscle on subsequent foot function during walking was assessed in healthy participants. WPS was delivered to the m . abductor hallucis ( m .AH) of the non-dominant foot during relaxed standing. 3-dimensional forefoot (FF) -- rearfoot (RF) coordination was quantified with a vector coding technique within separate periods of the stance phase to study WPS functional effects on foot motion. 4 types of coordinative strategies between the FF and RF were interpreted and compared PRE-to-POST-WPS for both the experimental and control feet. Bilateral electromyography (EMG) from m .AH was analysed during the intervention period for evidence of acute neuromuscular adaptation. The results showed that WPS significantly modulated FF-RF coordination during mid-stance, indicative of a more stable foot. Specifically, a statistically significant increase in FF eversion with concomitant RF inversion in the frontal plane and RF-dominated adduction in the transverse plane was observed. Subject-specific increases in post-stimulus m . AH EMG activation were observed but this was not reflected in an overall group effect. It is concluded that the structural integrity of the foot during walking is enhanced following an acute session of WPS and that this mechanical effect is most likely due to stimulation induced post-tetanic potentiation of synaptic transmission. [ABSTRACT FROM AUTHOR]

The effects of tenotomy present for two weeks on the post-tetanic responses of isolated fast (extensor digitorum longus) and slow (soleus) muscles were studied by isometric recording of muscle contraction in rats. After tetanic stimulation with bursts of 100 impulses at a frequency of 20 impulses/sec, the force of single fast muscle contractions exceeded the pretetanic level by 20-25% ( p < 0.05) in both intact and tenotomized muscles. In similar conditions, the slow muscle soleus showed a decrease in the amplitudes of single contractions, i.e., post-tetanic depression. Post-tetanic depression was not seen after tenotomy. Caffeine (4 mM) increased the force of single and tetanic contractions in control and tenotomized fast muscles, though no corresponding increase in post-tetanic responses were seen. In slow muscles, caffeine had no effect on the nature of post-tetanic responses. Dantrolene (10 μM) decreased the force of single and tetanic contractions but did not prevent the appearance of post-tetanic potentiation in fast muscles and depression in intact slow muscles. The fact that the phenomenon of post-tetanic potentiation disappeared after denervation of fast muscles within two weeks while it was present after tenotomy for as long as 40 days after surgery provides grounds for suggesting the existence of a potentiating factor which reaches muscles by axonal transport and increases single contractions. [ABSTRACT FROM AUTHOR]

Abstract: Elevated levels of the inflammatory cytokine interleukin-6 (IL-6) occur in a number of CNS disorders. However, little is known about how this condition affects CNS neuronal function. Transgenic mice that express elevated levels of IL-6 in the CNS show cognitive changes, increased propensity for hippocampal seizures and reduced number of inhibitory interneurons, suggesting that elevated levels of IL-6 can cause neuroadaptive changes that alter hippocampal function. To identify these neuroadaptive changes, we measured the levels of protein expression using Western blot analysis and synaptic function using field potential recordings in hippocampus from IL-6 transgenic mice (IL-6 tg) and their non-transgenic (non-tg) littermates. Western blot analysis showed enhanced levels of the GFAP and STAT3 in the IL-6 tg hippocampus compared with the non-tg hippocampus, but no difference for several other proteins. Field potential recordings of synaptic transmission at the Schaffer collateral to CA1 synapse showed enhanced dendritic excitatory postsynaptic potentials and somatic population spikes in the CA1 region of hippocampal slices from IL-6 tg mice compared with slices from non-tg littermate controls. No differences were observed for several forms of short-term and long-term synaptic plasticity between hippocampal slices from IL-6 tg and non-tg mice. These results demonstrate that elevated levels of IL-6 can alter mechanisms involved in the excitability of hippocampal neurons and synapses, an effect consistent with recent evidence indicating that elevated production of IL-6 plays an important role in conditions associated with seizure activity and in other impairments observed in CNS disorders with a neuroinflammatory component. [Copyright &y& Elsevier]

Abstract: Myosin filaments from many muscles are activated by phosphorylation of their regulatory light chains (RLCs). To elucidate the structural mechanism of activation, we have studied RLC phosphorylation in tarantula thick filaments, whose high-resolution structure is known. In the relaxed state, tarantula RLCs are ∼50% non-phosphorylated and 50% mono-phosphorylated, while on activation, mono-phosphorylation increases, and some RLCs become bi-phosphorylated. Mass spectrometry shows that relaxed-state mono-phosphorylation occurs on Ser35, while Ca2+-activated phosphorylation is on Ser45, both located near the RLC N-terminus. The sequences around these serines suggest that they are the targets for protein kinase C and myosin light chain kinase (MLCK), respectively. The atomic model of the tarantula filament shows that the two myosin heads (“free” and “blocked”) are in different environments, with only the free head serines readily accessible to kinases. Thus, protein kinase C Ser35 mono-phosphorylation in relaxed filaments would occur only on the free heads. Structural considerations suggest that these heads are less strongly bound to the filament backbone and may oscillate occasionally between attached and detached states (“swaying” heads). These heads would be available for immediate actin interaction upon Ca2 + activation of the thin filaments. Once MLCK becomes activated, it phosphorylates free heads on Ser45. These heads become fully mobile, exposing blocked head Ser45 to MLCK. This would release the blocked heads, allowing their interaction with actin. On this model, twitch force would be produced by rapid interaction of swaying free heads with activated thin filaments, while prolonged exposure to Ca2+ on tetanus would recruit new MLCK-activated heads, resulting in force potentiation. [Copyright &y& Elsevier]

J. Neurochem. (2010) 113, 943–951. Mammalian motor nerve terminals contain hundreds of thousands of synaptic vesicles, but only a fraction of these vesicles is immediately available for release, the remainder forming a reserve pool. The supply of vesicles is replenished through endocytosis, and newly formed vesicles are refilled with acetylcholine through a process that depends on the vesicular acetylcholine transporter (VAChT). During expression of short-term plasticity, quantal release can be increased, but it is unknown whether this reflects enhanced recruitment of vesicles from the reserve pool or rapid recycling. We examined spontaneous and evoked release of acetylcholine at endplates from genetically modified VAChT KDHOM mice that express approximately 30% of the normal level of VAChT to determine steps rate-limited by synaptic vesicle filling. Quantal content and quantal size were reduced in VAChT KDHOM mice compared with wild-type controls. Although high-frequency stimulation did not reduce quantal size further, the post-tetanic increase in end-plate potential amplitude or MEPP frequency was significantly smaller in VAChT KDHOM mice. This was the case even when tetanic depression was eliminated using an extracellular solution containing reduced Ca2+ and raised Mg2+. These results reveal the dependence of short-term plasticity on the level of VAChT expression and efficient synaptic vesicle filling. [ABSTRACT FROM AUTHOR]

Activity-dependent changes in the strength of synaptic connections in the hippocampus are central for cognitive processes such as learning and memory storage. In this study we reveal an activity-dependent presynaptic mechanism that is related to the modulation of synaptic plasticity. In acute mouse hippocampal slices, high-frequency stimulation (HFS) of the mossy fiber (MF)- CA3 pathway induced a strong and transient activation of extra-cellular-regulated kinase (ERK) in MF giant presynaptic terminals. Remarkably, pharmacological blockade of ERK disclosed a negative role of this kinase in the regulation of a presynaptic form of plastacity at MF-CA3 contacts. This ERK-mediated inhibition of post-tetanic enhancement (PTE) of MF-CA3 synapses was both frequency-and pathway-specific and was observed only with HFS at 50 Hz. Importantly, blockade of ERK was virtually ineffective on PTE of MF-CA3 synapses in mice lacking synapsin I, 1 of the major presynaptic ERK substrates, and triple knockout mice lacking all synapsin isoforms displayed PTE kinetics resembling that of wild-type mice under ERK inhibition. These findings reveal a form of short-term synaptic plasticity that depends on ERK and is finely tuned by the firing frequency of presynaptic neurons. Our results also demonstrate that presynaptic activation of the ERK signaling pathway plays part in the activity-dependent modulation of synaptic vesicle mobilization and transmitter release. [ABSTRACT FROM AUTHOR]

Abstract: We have previously demonstrated that L-type Ca2+ channels are involved in post-tetanic potentiation (PTP) of GABAergic IPSCs in cultured hippocampal neurons. Here we have used intracellular Fluo-3 to detect [Ca2+]i in single GABAergic boutons in response to stimulation that evokes PTP. During control stimulation of the presynaptic GABAergic neuron at 40 Hz for 1–2 s, ΔF/F 0 increased rapidly to a peak value and started to decline shortly after the train ended, returning to baseline within 10–20 s. The L-type channel blocker, isradipine (5 μM), had no significant effect on the amplitude or kinetics of the Ca2+ signal. Following blockade of N- and P/Q-type Ca2+-channels, the amplitude was reduced by 52.9±3%. Isradipine caused a reduction of the remaining response (by 26.6±5%, P <0.01), that was fully reversible on washing. The L-type channel “agonist”, BayK 8644 (8 μM), caused a significant enhancement of the peak (by 18.7%±7%, P <0.05). The rising phase of the Ca2+ signal, which is related to the rate of entry of Ca2+ into the bouton, was decreased by isradipine (by 25.5±6%, P <0.05) and enhanced by BayK 8644 (by 45.2%±16%, P <0.05). These Ca2+ imaging experiments support the putative role of L-type channels in PTP of GABAergic synapses on cultured hippocampal neurons. We expect L-channels to be few in number, although they may couple strongly to intracellular signalling cascades that could amplify a signal that regulates synaptic vesicle turnover in the GABAergic boutons. [Copyright &y& Elsevier]

Abstract: In neurons, as in other excitable cells, mitochondria extrude Ca2+ ions from their matrix in exchange with cytosolic Na+ ions. This exchange is mediated by a specific transporter located in the inner mitochondrial membrane, the mitochondrial Na+/Ca2+ exchanger (NCXmito). The stoichiometry of NCXmito-operated Na+/Ca2+ exchange has been the subject of a long controversy, but evidence of an electrogenic 3 Na+/1 Ca2+ exchange is increasing. Although the molecular identity of NCXmito is still undetermined, data obtained in our laboratory suggest that besides the long-sought and as yet unfound mitochondrial-specific NCX, the three isoforms of plasmamembrane NCX can contribute to NCXmito in neurons and astrocytes. NCXmito has a role in controlling neuronal Ca2+ homeostasis and neuronal bioenergetics. Indeed, by cycling the Ca2+ ions captured by mitochondria back to the cytosol, NCXmito determines a shoulder in neuronal [Ca2+]c responses to neurotransmitters and depolarizing stimuli which may then outlast stimulus duration. This persistent NCXmito-dependent Ca2+ release has a role in post-tetanic potentiation, a form of short-term synaptic plasticity. By controlling [Ca2+]m NCXmito regulates the activity of the Ca2+-sensitive enzymes pyruvate-, α-ketoglutarate- and isocitrate-dehydrogenases and affects the activity of the respiratory chain. Convincing experimental evidence suggests that supraphysiological activation of NCXmito contributes to neuronal cell death in the ischemic brain and, in epileptic neurons coping with seizure-induced ion overload, reduces the ability to reestablish normal ionic homeostasis. These data suggest that NCXmito could represent an important target for the development of new neurological drugs. [Copyright &y& Elsevier]

Previous studies indicate that boutons from the same axon exhibit distinct Ca2+dynamics depending on the postsynaptic targets. Mossy fibers of hippocampal granule cells innervate synaptic targets via morphologically distinct boutons. We investigated mitochondrial involvement in the generation of post-tetanic residual Ca2+(Cares ) at large and small en passant mossy fiber boutons (MFBs). Mitochondria limited the [Ca2+]i build-up during high-frequency stimulation (HFS) at large MFBs, but not at small MFBs. The amount of Cares, quantified as a time integral of residual [Ca2+]i , was significantly larger at large MFBs than at small MFBs, and that at large MFBs was substantially attenuated by inhibitors of mitochondrial Ca2+ uniporter and mitochondrial Na+/Ca2+ exchanger (mitoNCX). In contrast, blockers of mitoNCX had no effect on the Cares at small MFBs. Post-tetanic Cares has been proposed as a mechanism for post-tetanic potentiation (PTP). We examined mitochondrial involvement in PTP at mossy fiber synapses on hilar mossy cells (MF→MC synapse) and on hilar interneurons (MF→HI synapse), which are presumably innervated via large and small MFBs, respectively. Consistent with the differential contribution of mitochondria to Cares at large and small MFBs, mitoNCX blockers significantly reduced the PTP at the MF→MC synapse, but not at the MF→HI synapse. In contrast, protein kinase C (PKC) inhibitors significantly reduced the PTP at MF→HI synapse, but not at the MF→MC synapse. These results indicate that mitochondria- and PKC-dependent PTP are expressed at distinct hilar mossy fiber synapses depending on postsynaptic targets. [ABSTRACT FROM AUTHOR]

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs. [Copyright &y& Elsevier]

Abstract: We have previously shown that post-tetanic potentiation (PTP) of GABAergic IPSCs in cultured hippocampal neurons involves activation of L-type Ca2+ channels. Although there is little Ca2+ entry by this route, it is possible that L-type Ca2+ channels mediate an increase in probability of release (Pr) by a mechanism that remains dormant in the absence of stimulation. We have tested this hypothesis in the present study using dual whole-cell patch clamp recordings. IPSCs were evoked by low-frequency stimulation (LFS; 0.2 Hz) of presynaptic GABAergic neurons. Run-down was corrected by linear regression. Following tetanic stimulation (80 pulses at 40 Hz), the presence of PTP was probed by resuming LFS after various post-tetanic intervals (PTI). To control for possible effects associated with LFS, the train and PTI were replaced by corresponding pauses. Following pauses ≥16 s, the first IPSC was significantly increased by 20–25% (P <0.01, paired t-test). These post-pause responses were subtracted from IPSCs following tetanic stimulation. Following correction, PTP was greatest (∼50%) after the shortest PTI (4 s) and IPSC amplitudes declined back to the baseline value over 1–2 min. With a PTI of 16 s, the first IPSC was potentiated to the same level as that to which PTP with a PTI of 4 s had decayed with continued LFS. There was no significant PTP with PTIs of 64 and 128 s. Since PTP decays entirely in the absence of stimulation, it is concluded that the process(es) mediating the increase in vesicular Pr appear to be time-dependent, but not use-dependent. [Copyright &y& Elsevier]

The mesocortical dopamine (DA) input to the prefrontal cortex (PFC) is crucial for processing short-term working memory (STWM) to guide forthcoming behavior. Short-term plasticity-like post-tetanic potentiation (PTP, < 3 min) and short-term potentiation (STP, < 10 min) may underlie STWM. Using whole-cell voltage-clamp recordings, mixed glutamatergic excitatory postsynaptic currents (EPSCs) evoked by layer III or layer V stimulation (0.5 or 0.067 Hz) were recorded from layer V pyramidal neurons. With 0.5 Hz basal stimulation of layer III, brief tetani (2 × 50 Hz) induced a homosynaptic PTP (decayed: ∼1 min). The D1-like antagonist SCH23390 (1 µ m) increased the PTP amplitude and decay time without inducing changes to the tetanic response. The tetani may evoke endogenous DA release, which activates a presynaptic D1-like receptor to inhibit glutamate release to modulate PTP. With a slower (0.067 Hz) basal stimulation, the same tetani induced STP (lasting ∼4 min, but only at 2× intensity only) that was insignificantly suppressed by SCH23390. With stimulation of layer-V→V inputs at 0.5 Hz, layer V tetani yielded inconsisitent responses. However, at 0.067 Hz, tetani at double the intensity resulted in an STP (lasting ∼6 min), but a long-term depression after SCH23390 application. Endogenous DA released by tetanic stimulation can interact with a D1-like receptor to induce STP in layer V→V synapses that receive slower (0.067 Hz) frequency inputs, but suppresses PTP at layer III→V synapses that receive higher (0.5 Hz) frequency inputs. This D1-like modulation of layer- and frequency-specific synaptic responses in the PFC may contribute to STWM processing. [ABSTRACT FROM AUTHOR]

The effects of presynaptic guanosine-5'-O-(3-thio)triphosphate (GTPγS) on GABAergic inhibitory postsynaptic currents (IPSCs) were studied in cultured hippocampal neurons using whole-cell recordings. Inclusion of GTPγS (0.5–1 mM) in the presynaptic electrode reduced both the amplitude and paired-pulse depression of IPSCs, indicating that the probability of GABA-release had been reduced. Presynaptic GTPγS increased the depression of IPSCs by the GABAB-receptor-agonist baclofen (10 µM), and the effect of baclofen was poorly reversible after washing. Stimulation of the GABAergic neuron at 80 Hz for 1 s was accompanied by tetanic depression of the IPSCs by 52±6% and was followed by post-tetanic potentiation (PTP), reaching a peak value of 71±21% and lasting about 100 s. IPSCs evoked after tetanic stimulation were depressed and PTP was absent when tetanic stimulation was applied within 3 min after starting injection of GTPγS into the presynaptic neuron. At longer times, basal release underlying a single IPSC was depressed. This affected the ratios recorded in response to tetanic stimulations such that tetanic depression was abolished, while PTP increased to 117±34%. In conclusion, GTPγS reduces the probability of GABA-release in both a use- and time-dependent manner, most likely through an inhibitory action on presynaptic Ca2+-influx through voltage-gated Ca2+ channels or an interaction with small GTP-binding proteins in the nerve terminals. [ABSTRACT FROM AUTHOR]