Synaptic Facilitation Research Articles

Synaptotagmin 7 Mediates Both Facilitation and Asynchronous Release at Granule Cell Synapses.

When an action potential invades a presynaptic terminal it evokes large, brief Ca2+ signals that trigger vesicle fusion within milliseconds that is followed by a small residual Ca2+ (Cares) signal. At many synapses Cares produces synaptic facilitation that lasts up to hundreds of milliseconds and, although less common, Cares can also evoke asynchronous release (AR) that persists for tens of milliseconds. The properties of facilitation and AR are very different, which suggests that they are mediated by distinct mechanisms. However, recently it has been shown that the slow calcium sensor synaptotagmin 7 (Syt7) mediates facilitation at many synapses where AR does not occur, and conversely Syt7 can mediate AR without mediating facilitation. Here we study cerebellar granule cell synapses onto stellate cells and Purkinje cells in mice of both sexes to assess the role of Syt7 in these phenomena at the same synapse. This is of particular interest at granule cell synapses where AR is much more calcium dependent and shorter-lived than facilitation. We find that Syt7 can mediate these two processes despite their divergent properties. In Syt7 knock-out animals, facilitation and AR are smaller and shorter lived than in wild-type animals, even though the initial probability of release and Cares signals are unchanged. Although there are short-lived Syt7-independent mechanisms that mediate facilitation and AR in Syt7 KO animals, we find that at granule cell synapses AR and facilitation are both mediated primarily by Syt7.SIGNIFICANCE STATEMENT At synapses made by cerebellar granule cells, presynaptic activity elevates calcium for tens of milliseconds, which in turn evokes both asynchronous release (AR) and synaptic facilitation. AR is more calcium sensitive and shorter-lived than facilitation at these synapses, suggesting that they are mediated by different mechanisms. However, we find that the slow calcium sensor synaptotagmin 7 mediates both of these phenomena. Small, rapidly decaying components of AR and facilitation are present in Syt7 KO animals, indicating that additional mechanisms can contribute to both AR and facilitation at these synapses.

Adaptive control of structural balance for complex dynamical networks based on dynamic coupling of nodes

In the existing research results of the complex dynamical networks controlled, the controllers are mainly used to guarantee the synchronization or stabilization of the nodes’ state, and the terms coupled with connection relationships may affect the behaviors of nodes, this obviously ignores the dynamic common behavior of the connection relationships between the nodes. In fact, from the point of view of large-scale system, a complex dynamical network can be regarded to be composed of two time-varying dynamic subsystems, which can be called the nodes subsystem and the connection relationships subsystem, respectively. Similar to the synchronization or stabilization of the nodes subsystem, some characteristic phenomena can be also emerged in the connection relationships subsystem. For example, the structural balance in the social networks and the synaptic facilitation in the biological neural networks. This paper focuses on the structural balance in dynamic complex networks. Generally speaking, the state of the connection relationships subsystem is difficult to be measured accurately in practical applications, and thus it is not easy to implant the controller directly into the connection relationships subsystem. It is noted that the nodes subsystem and the relationships subsystem are mutually coupled, which implies that the state of the connection relationships subsystem can be affected by the controllable state of nodes subsystem. Inspired by this observation, by using the structural balance theory of triad, the controller with the parameter adaptive law is proposed for the nodes subsystem in this paper, which may ensure the connection relationship matrix to approximate a given structural balance matrix in the sense of the uniformly ultimately bounded (UUB). That is, the structural balance may be obtained by employing the controlling state of the nodes subsystem. Finally, the simulations are used to show the validity of the method in this paper.

The structural balance analysis of complex dynamical networks based on nodes' dynamical couplings.

The nodes and their connection relationships are the two main bodies for dynamic complex networks. In existing theoretical researches, the phenomena of stabilization and synchronization for complex dynamical networks are generally regarded as the dynamic characteristic behaviors of the nodes, which are mainly caused by coupling effect of connection relationships between nodes. However, the connection relationships between nodes are also one main body of a time-varying dynamic complex network, and thus they may evolve with time and maybe show certain characteristic phenomena. For example, the structural balance in the social networks and the synaptic facilitation in the biological neural networks. Therefore, it is important to investigate theoretically the reasons in dynamics for the occurrence. Especially, from the angle of large-scale systems, how the dynamic behaviors of nodes (such as the individuals, neurons) contribute to the connection relationships is one of worthy research directions. In this paper, according to the structural balance theory of triad proposed by F. Heider, we mainly focus on the connection relationships body, which is regarded as one of the two subsystems (another is the nodes body), and try to find the dynamic mechanism of the structural balance with the internal state behaviors of the nodes. By using the Riccati linear matrix differential equation as the dynamic model of connection relationships subsystem, it is proved under some mathematic conditions that the connection relationships subsystem is asymptotical structural balance via the effects of the coupling roles with the internal state of nodes. Finally, the simulation example is given to show the validity of the method in this paper.

Модулирующее влияние адреналина на развитие стероидной миопатии у белых крыс, индуцированной длительным введением гидрокортизона

Цель исследования - изучение эффективности адреналина в компенсации негативных эффектов длительно вводимого гидрокортизона на скелетную мышцу смешанного типа. Методика. Эксперименты проводились на половозрелых крысах-самках (190-220 г), разделенных на 3 группы: контрольную (n = 10), I опытную (n = 10, ежедневно на протяжении 30 сут. получали гидрокортизона ацетат, Г-группа) и II опытную (n = 10, ежедневно на протяжении 30 сут. получали гидрокортизона ацетат в комплексе с адреналина гидрохлоридом, (Г+А)-группа). Гидрокортизона ацетат («Фармак», Украина) вводили внутрибрюшинно в дозе, адекватной терапевтической для человека, - 3 мг/кг. Адреналина гидрохлорид («Здоровье», Украина) вводили подкожно в дозе 0,2 мг/кг. На наркотизированных животных (тиопентал натрия, 100 мг/кг) с помощью методов электромиографии и миографии изучали параметры функционального состояния передней большеберцовой мышцы в условиях ее сокращения, индуцированного раздражением сверхпороговым электрическим током малоберцового нерва. Результаты. Длительное (в течение 30 сут.) введение гидрокортизона вызывало развитие симптомов стероидной миопатии, о чем свидетельствует появление низкоамплитудных М-ответов нормальной длительности, возрастание частоты полифазных потенциалов (до 30%), уменьшение количества активируемых двигательных единиц (на 33%) и мышечной массы (на 14%). Гидрокортизоновый гиперкортицизм сопровождался удлинением латентного периода одиночного сокращения передней большеберцовой мышцы (на 37%) и фазы его укорочения (на 20%), уменьшением амплитуды одиночных сокращений (на 32%), объема выполненной мышцей внешней работы (на 40%) и развиваемой мощности (на 41%) при тетаническом сокращении. Отмечены нарушения в целостном процессе нервно-мышечной передачи, что проявлялось в уменьшении степени ее надежности (у 30% особей), выраженном облегчении (более 85% у 50% особей) или депрессии (до -42% у 40% особей) при стимуляции нервно-мышечного аппарата с оптимальной частотой (30 имп/с). Адреналин, вводимый в комплексе с гидрокортизоном, предотвращал появление ряда симптомов миопатии, таких, как снижение амплитуды М-ответов, уменьшение количества активируемых двигательных единиц мышцы, ее массы, внешней работы и мощности, а также обусловливал уменьшение частоты генерации полифазных М-ответов (с 30% до 10%). Кроме того, адреналин ослаблял негативный эффект гидрокортизона на синаптический аппарат, что проявлялось в уменьшении частоты встречаемости сниженной надежности синаптической передачи (с 30% до 10%), выраженного ее облегчения (с 50% до 20%) и депрессии (с 40% до 10%) у животных (Г+А)-группы в сравнении с Г-группой. Заключение. Полученные в модельных экспериментах на животных в условиях in situ данные свидетельствуют о способности адреналина эффективно компенсировать ряд негативных эффектов, развивающихся в скелетной мышце при длительном введении гидрокортизона. Based on the beneficial effect of chronic adrenergic stimulation on the neuromuscular apparatus function, the aim of this study was to evaluate efficacy of adrenaline at therapeutic doses in compensation for adverse effects of chronically administered hydrocortisone on mixed-fiber type skeletal muscles ( m. tibialis anterior ). Method. Experiments were performed on sexually mature female rats (190-220 g) divided into 3 groups: control (n = 10), experimental group 1 (H group, n = 10, hydrocortisone acetate, for 30 days daily), and experimental group 2 (H+A group, n = 10, hydrocortisone acetate in combination with adrenaline hydrochloride, for 30 days daily). Hydrocortisone acetate (Farmak, Ukraine) was injected i.p. at a dose of 0.2 mg/kg, which was equivalent to the human therapeutic dose of 3 mg/kg. Adrenaline hydrochloride (Zdorovje, Ukraine) was injected s.c. at a dose of 0.2 mg/kg. Parameters of the tibialis anterior muscle function were studied on anesthetized animals (sodium thiopental, 100 mg/kg) using electromyography and myography methods. Muscle contractions were induced by suprathreshold electrical stimulation of the fibular nerve. Results. Chronic administration (30 days) of hydrocortisone caused symptoms of steroid myopathy evident as low-amplitude M-waves of normal duration, increased frequency of polyphase potentials (by 30%), decreased quantity of activated motor units (by 33%), and decreased muscle mass (by 14%). Hydrocortisone-induced hypercorticoidism was associated with prolonged latent period (by 37%) and shortening phase (by 20%) and decreased amplitude (by 32%), amount of muscular external work (by 40%) in a single tibialis anterior muscle contraction, and decreased muscular power (by 41%) developed in a tetanic contraction. Following repeated hydrocortisone injections, the overall process of neuromuscular transmission was disturbed, which was evident as its impaired reliability (30% of rats) and pronounced facilitation (>85% in 50% of rats) or depression (<-42% in 40% of rats) at an optimum stimulation frequency (30 imp/s). Adrenaline administered in combination with hydrocortisone prevented formation of myopathy symptoms, such as decreases in the M-wave amplitude, number of activated motor units, muscle weight, external work and power, and it also decreased the frequency of polyphase M-waves (from 30% to 10%). In addition, adrenaline attenuated the adverse effect of hydrocortisone on the synaptic apparatus by decreasing the incidence of reduced reliability of synaptic transmission (from 30% to 10%), facilitation (from 50% to 20%), and depression (from 40% to 10%) in the H+A-group compared to the H group. Conclusion. The experimental data obtained in model experiments on animals in situ support the adrenaline ability to effectively compensate for a number of adverse effects of chronic hydrocortisone treatment on the skeletal muscle.

Neuronal inhibition and synaptic plasticity of basal ganglia neurons in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson's disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1-100 Hz, 100 µA, 0.3 ms, 50-60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long-train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed-loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation.

A gradient of frequency-dependent synaptic properties along the longitudinal hippocampal axis

BackgroundThe hippocampus is a functionally heterogeneous brain structure and specializations of the intrinsic neuronal network may crucially support the functional segregation along the longitudinal axis of the hippocampus. Short-term synaptic plasticity plays fundamental roles in information processing and may be importantly involved in diversifying the properties of local neuronal network along the hippocampus long axis. Therefore, we aimed to examine the properties of the cornu ammonis 1 (CA1) synapses along the entire dorsoventral axis of the rat hippocampus using field excitatory postsynaptic potentials from transverse rat hippocampal slices and a frequency stimulation paradigm.ResultsApplying a ten-pulse stimulus train at frequencies from 0.1 to 100 Hz to the Schaffer collaterals we found a gradually diversified pattern of frequency-dependent synaptic effects along the dorsoventral hippocampus axis. The first conditioned response was facilitated along the whole hippocampus for stimulus frequencies 10–40 Hz. However, steady-state responses or averaged responses generally ranged from maximum synaptic facilitation in the most dorsal segment of the hippocampus to maximum synaptic depression in the most ventral segment of the hippocampus. In particular, dorsal synapses facilitated for stimulus frequency up to 50 Hz while they depressed at higher frequencies (75–100 Hz). Facilitation at dorsal synapses was maximal at stimulus frequency of 20 Hz. On the contrary, the most ventral synapses showed depression regardless of the stimulus frequency, only displaying a transient facilitation at the beginning of 10–50 Hz stimulation. Importantly, the synapses in the medial hippocampus displayed a transitory behavior. Finally, as a whole the hippocampal synapses maximally facilitated at 20 Hz and increasingly depressed at 50–100 Hz.ConclusionThe short-term synaptic dynamics change gradually along the hippocampal long axis in a frequency-dependent fashion conveying distinct properties of information processing to successive segments of the structure, thereby crucially supporting functional segregation along the dorsoventral axis of the hippocampus.

The role of Ca2+‐dependent K+‐ channels at the rat corticostriatal synapses revealed by paired pulse stimulation

Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located KV and KIR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here, we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum. By using a paired pulse protocol, we induced synaptic facilitation before applying either BK- or SK-specific toxins. Thus, we found that blockage of BKCa with iberiotoxin (10 nM) reduces synaptic facilitation and increases the amplitude of the EPSP, while exposure to SK-blocker apamin (100 nM) has no effect. Additionally, we induced train action potentials on striatal MSN by current injection before and after the exposure to KCa toxins. We found that the action potential becomes broader when the MSN is exposed to iberiotoxin, although it has no impact on frequency. In contrast, exposure to apamin results in loss of afterhyperpolarization phase and an increase of spike frequency. Therefore, we concluded that postsynaptic SK channels are involved in afterhyperpolarization and modulation of spike frequency while the BK channels are involved on the late repolarization phase of the action potential. Altogether, our results show that calcium-dependent potassium channels modulate both input towards and output from the striatum.

The genetics of PKMζ and memory maintenance.

Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mζ (PKMζ) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMζ has been challenged by genetic data from PKMζ-knockout mice showing intact LTP and long-term memory. Moreover, the PKMζ inhibitor peptide ζ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMζ-antisense approach showed that LTP and long-term memory in PKMζ-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCι/λ. Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCι/λ knockdown disrupted short-term memory, whereas PKMζ knockdown specifically erased long-term memory. Third, conditional PKCι/λ knockout induced compensation by rapidly activating PKMζ to preserve short-term memory. Fourth, a dominant-negative approach in the model system Aplysia revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMζ is the principal PKC isoform that maintains LTP and long-term memory. PKCι/λ can compensate for PKMζ, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMζ malfunctions.

Positive feedback and synchronized bursts in neuronal cultures.

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

Status epilepticus induced by pentylenetetrazole increases short-term synaptic facilitation in the hippocampus of juvenile rats.

We studied the effect of status epilepticus (SE) on short-term synaptic plasticity. The amplitudes of field potentials in response to extracellular stimulation of the Schaffer collaterals were recorded in hippocampal slices. Subtle modifications were revealed on day 1 after SE, whereas on days 3 and 7 we did not find any differences from the control. These data show that, one day after SE, the probability of a transmitter release in hippocampal synapses decreases that serves as a compensatory mechanism, which prevents seizure activity.

The effects of dynamical synapses on firing rate activity: a spiking neural network model.

Accumulating evidence relates the fine-tuning of synaptic maturation and regulation of neural network activity to several key factors, including GABAA signaling and a lateral spread length between neighboring neurons (i.e., local connectivity). Furthermore, a number of studies consider short-term synaptic plasticity (STP) as an essential element in the instant modification of synaptic efficacy in the neuronal network and in modulating responses to sustained ranges of external Poisson input frequency (IF). Nevertheless, evaluating the firing activity in response to the dynamical interaction between STP (triggered by ranges of IF) and these key parameters invitro remains elusive. Therefore, we designed a spiking neural network (SNN) model in which we incorporated the following parameters: local density of arbor essences and a lateral spread length between neighboring neurons. We also created several network scenarios based on these key parameters. Then, we implemented two classes of STP: (1) short-term synaptic depression (STD) and (2) short-term synaptic facilitation (STF). Each class has two differential forms based on the parametric value of its synaptic time constant (either for depressing or facilitating synapses). Lastly, we compared the neural firing responses before and after the treatment with STP. We found that dynamical synapses (STP) have a critical differential role on evaluating and modulating the firing rate activity in each network scenario. Moreover, we investigated the impact of changing the balance between excitation (E) and inhibition (I) on stabilizing this firing activity.

Humidity-Dependent Synaptic Plasticity for Proton Gated Oxide Synaptic Transistor

Indium-tin-oxide synaptic transistors using proton conducting nanogranular phosphorosilicate glass as gate dielectric are fabricated. Humidity-dependent proton gating behaviors are observed. Moreover, synaptic plasticities are mimicked on the proton gated oxide synaptic transistors. Interestingly, enhanced synaptic facilitation is observed at higher relative humidity originated from the strengthened proton gating. An oxide synaptic transistor with humidity-dependent synaptic plasticities may find potential applications in neuromorphic platforms.

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

Excitatory-inhibitory imbalance in the brain of the wobbler mouse model of amyotrophic lateral sclerosis substantiated by riluzole and diazepam.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. So far, no cure exists, prompting studies in disease mechanisms to facilitate development of new treatment strategies. In this study, we employed the wobbler mouse model of ALS focusing on a symptomatic group of animals. We studied the neurophysiological changes conferred by riluzole or diazepam application, two drugs employed in ALS. Riluzole is an antiglutamatergic agent and the only drug to offer some effect on the life expectancy of ALS patients. To target the inhibitory system, we utilized diazepam as a GABAergic modulator. Acute brain slices were prepared from the wobbler mouse model and analyzed using extracellular field recordings in the hippocampus. During Schaffer collateral stimulation, riluzole caused a marked reduction in the paired-pulse ratio (p<0.0001). Importantly, this reduction was more pronounced in wobbler slices (e.g. 184.2±8.9% at 20ms interval without riluzole, and 124.3±9.8% in the presence of riluzole) compared to control slices (at 20ms: from 198.7±5.8% to 160.5±6.7%). Diazepam caused less pronounced effects at wobbler slices and reduced the paired-pulse ratio more in control animals compared to wobbler individuals (p<0.0001). Comparable results were obtained during trains of stimulations (10 pulses at 20Hz). Importantly, paired-pulse ratios as well as synaptic facilitation were overall similar in control and wobbler slices, without the drugs present, indicating that the differences were only revealed pharmacologically. In summary, the present data support excitatory-inhibitory imbalances in the brain of the wobbler mouse and further consolidate this mouse as an animal model of ALS.

SNAP-25 phosphorylation at Ser187 regulates synaptic facilitation and short-term plasticity in an age-dependent manner

Neurotransmitter release is mediated by the SNARE complex, but the role of its phosphorylation has scarcely been elucidated. Although PKC activators are known to facilitate synaptic transmission, there has been a heated debate on whether PKC mediates facilitation of neurotransmitter release through phosphorylation. One of the SNARE proteins, SNAP-25, is phosphorylated at the residue serine-187 by PKC, but its physiological significance has been unclear. To examine these issues, we analyzed mutant mice lacking the phosphorylation of SNAP-25 serine-187 and found that they exhibited reduced release probability and enhanced presynaptic short-term plasticity, suggesting that not only the release process, but also the dynamics of synaptic vesicles was regulated by the phosphorylation. Furthermore, it has been known that the release probability changes with development, but the precise mechanism has been unclear, and we found that developmental changes in release probability of neurotransmitters were regulated by the phosphorylation. These results indicate that SNAP-25 phosphorylation developmentally facilitates neurotransmitter release but strongly inhibits presynaptic short-term plasticity via modification of the dynamics of synaptic vesicles in presynaptic terminals.

Short-term facilitation and depression of transmitter release at amphibian sympathetic ganglionic cells – Mathematical/computational modeling

There have been few investigations of the short-term plasticity of synaptic transmission at amphibian sympathetic ganglionic cells where the frequency of miniature excitatory postsynaptic potentials is too low to measure an accurate quantum size. This has made it difficult to investigate the mechanism of synaptic transmission at the ganglionic cells by quantal analysis. A theoretical equation, therefore, is proposed. This equation is based on the premise that transmitter release is due to the product of two factors: intracellular calcium ([Ca2+]i) and acetylcholine (ACh), which is a readily releasable transmitter. The equation accounts for the mechanism of synaptic facilitation and depression of transmitter release at the ganglionic cells in the paired-pulse experiments.The purpose of the present experiment is to investigate whether the equation accounts for the mechanism of short-term plasticity of synaptic transmission produced by a train of pulses at the ganglionic cells. Trains of excitatory postsynaptic current (EPSC) were recorded, and the ratios of the nth EPSC induced by the nth pulse to the initial EPSC were analyzed by the equation.The results indicated that the mechanism of short-term facilitation and depression was interpreted by the equation, which met the following two requirements: [Ca2+]i consisting of two components of residual Ca2+ and the mobilization rate of ACh which accelerated as stimulus frequencies increased. The findings were consistent with those clarified by the quantal analysis.It is suggested that the theoretical equation is also useful for the investigation of the effect of chemical substances on synaptic transmission.

Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity

Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of voltage-gated Ca2+ channel (VGCC) α1 subunits can generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission, which crucially depends on VGCCs, is unclear. Here, we investigate how two major splice isoforms of P/Q-type VGCCs (Cav2.1[EFa/b]) regulate presynaptic plasticity in hippocampal neurons. We find that the efficacy of P/Q-type VGCC isoforms in supporting synaptic transmission is markedly different, with Cav2.1[EFa] promoting synaptic depression and Cav2.1[EFb] synaptic facilitation. Following a reduction in network activity, hippocampal neurons upregulate selectively Cav2.1[EFa], the isoform exhibiting the higher synaptic efficacy, thus effectively supporting presynaptic homeostatic plasticity. Therefore, the balance between VGCC splice variants at the synapse is a key factor in controlling neurotransmitter release and presynaptic plasticity.

SOLUBLE AMYLOID PRECURSOR PROTEIN IS AN ISOFORM-SPECIFIC GABA(B) RECEPTOR LIGAND THAT SUPPRESSES SYNAPTIC RELEASE PROBABILITY

Amyloid Precursor Protein has been extensively studied for its generation of the amyloid-beta peptide implicated in Alzheimer's disease. However, the physiological function of APP and its processing products remains elusive. Soluble APP (sAPP), the product of APP ectodomain shedding, is sufficient to restore synaptic deficits in APP knockout mice, suggesting the presence of a synaptic receptor for sAPP. However, the putative synaptic receptor for sAPP has yet to be identified. To identify candidate synaptic interactors for sAPP, we performed a shotgun proteomics screen using purified sAPP-Fc as bait and synaptosome extracts from rat brain as prey. We performed cell surface binding assays and isothermal titration calorimetry to validate binding of sAPP to GABA(B) receptors. To access if sAPP modulates GABA(B)R function, we analyzed both miniature excitatory postsynaptic currents (mEPSCs) and exocytosis of FM1–43 labeled vesicles in hippocampal cultures in response to acute application of sAPP and GABA(B)R antagonists. Finally, we performed extracellular recordings on acute hippocampal slices to analyze GABA(B)R-dependent effects of sAPP on synaptic transmission at the CA3-CA1 pathway. Our proteomics screen led to the identification of GABA(B) receptor as a synaptic APP interactor. A conserved 17aa peptide within the extension domain of sAPP directly interacts with the sushi-1 domain specific to the GABA(B)R1a isoform. sAPP reduces both the frequency of mEPSCs and synaptic vesicle exocytosis in hippocampal cultures. The 17aa GABA(B)R1a-specific binding region of sAPP is both required and sufficient to suppress synaptic release. Finally, sAPP decreases the strength of basal synaptic transmission and enhances short-term synaptic facilitation in hippocampal slices, implying a reduced probability of release. The effect of sAPP on synaptic release both in cultures and in slices is blocked by pretreatment with a GABA(B)R antagonist, demonstrating that sAPP decreases the probability of release via presynaptic GABA(B) receptors. sAPP directly interacts with GABA(B)R1a and acts a positive modulator of GABA(B) receptor signaling to reduce synaptic release probability.

Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol.

Developing treatment strategies to enhance memory is an important goal of neuroscience research. Activation of multiple biochemical signaling cascades, such as the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways, is necessary to induce long-term synaptic facilitation (LTF), a correlate of long-term memory (LTM). Previously, a computational model was developed which correctly predicted a novel enhanced training protocol that augmented LTF by searching for the protocol with maximal overlap of PKA and ERK activation. The present study focused on pharmacological approaches to enhance LTF. Combining an ERK activator, NSC, and a PKA activator, rolipram, enhanced LTF to a greater extent than did either drug alone. An even greater increase in LTF occurred when rolipram and NSC were combined with the Enhanced protocol. These results indicate superior memory can be achieved by enhanced protocols that take advantage of the structure and dynamics of the biochemical cascades underlying memory formation, used in conjunction with combinatorial pharmacology.

Mixed protonic and electronic conductors hybrid oxide synaptic transistors

Mixed ionic and electronic conductor hybrid devices have attracted widespread attention in the field of brain-inspired neuromorphic systems. Here, mixed protonic and electronic conductor (MPEC) hybrid indium-tungsten-oxide (IWO) synaptic transistors gated by nanogranular phosphorosilicate glass (PSG) based electrolytes were obtained. Unique field-configurable proton self-modulation behaviors were observed on the MPEC hybrid transistor with extremely strong interfacial electric-double-layer effects. Temporally coupled synaptic plasticities were demonstrated on the MPEC hybrid IWO synaptic transistor, including depolarization/hyperpolarization, synaptic facilitation and depression, facilitation-stead/depression-stead behaviors, spiking rate dependent plasticity, and high-pass/low-pass synaptic filtering behaviors. MPEC hybrid synaptic transistors may find potential applications in neuron-inspired platforms.