The computational role of short-term plasticity and the balance of excitation and inhibition in neural microcircuits: experimental and theoretical analysis

The computations performed by the brain ultimately rely on the functional connectivity between neurons embedded in complex networks. It is well known that the neuronal connections, the synapses, are plastic, i.e. the contribution of each presynaptic neuron to the firing of a postsynaptic neuron can be independently adjusted. The modulation of effective synaptic strength can occur on time scales that range from tens or hundreds of milliseconds, to tens of minutes or hours, to days, and may involve pre- and/or post-synaptic modifications. The collection of these mechanisms is generally believed to underlie learning and memory and, hence, it is fundamental to understand their consequences in the behavior of neurons.(...)

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

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.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

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.

Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice

Cell adhesion molecules (CAMs) are known to be involved in a variety of developmental processes that play key roles in the establishment of synaptic connectivity during embryonic development, but recent evidence implicates the same molecules in synaptic plasticity of the adult. In the present study, we have used neural CAM (NCAM)-deficient mice, which have learning and behavioral deficits, to evaluate NCAM function in the hippocampal mossy fiber system. Morphological studies demonstrated that fasciculation and laminar growth of mossy fibers were strongly affected, leading to innervation of CA3 pyramidal cells at ectopic sites, whereas individual mossy fiber boutons appeared normal. Electrophysiological recordings performed in hippocampal slice preparations revealed that both basal synaptic transmission and two forms of short-term plasticity, i.e., paired-pulse facilitation and frequency facilitation, were normal in mice lacking all forms of NCAM. However, long-term potentiation of glutamatergic excitatory synapses after brief trains of repetitive stimulation was abolished. Taken together, these results strongly suggest that in the hippocampal mossy fiber system, NCAM is essential both for correct axonal growth and synaptogenesis and for long-term changes in synaptic strength.

Distinct short-term plasticity at two excitatory synapses in the hippocampus

A single mossy fiber input contains several release sites and is located on the proximal portion of the apical dendrite of CA3 neurons. It is, therefore, well suited to exert a strong influence on pyramidal cell excitability. Accordingly, the mossy fiber synapse has been referred to as a detonator or teacher synapse in autoassociative network models of the hippocampus. The very low firing rates of granule cells [Jung, M. W. & McNaughton, B. L. (1993) Hippocampus 3, 165–182], which give rise to the mossy fibers, raise the question of how the mossy fiber synapse temporally integrates synaptic activity. We have therefore addressed the frequency dependence of mossy fiber transmission and compared it to associational/commissural synapses in the CA3 region of the hippocampus. Paired pulse facilitation had a similar time course, but was 2-fold greater for mossy fiber synapses. Frequency facilitation, during which repetitive stimulation causes a reversible growth in synaptic transmission, was markedly different at the two synapses. At associational/commissural synapses facilitation occurred only at frequencies greater than once every 10 s and reached a magnitude of about 125% of control. At mossy fiber synapses, facilitation occurred at frequencies as low as once every 40 s and reached a magnitude of 6-fold. Frequency facilitation was dependent on a rise in intraterminal Ca2+ and activation of Ca2+/calmodulin-dependent kinase II, and was greatly reduced at synapses expressing mossy fiber long-term potentiation. These results indicate that the mossy fiber synapse is able to integrate granule cell spiking activity over a broad range of frequencies, and this dynamic range is substantially reduced by long-term potentiation.

Very short-term plasticity in hippocampal synapses

Hippocampal pyramidal neurons often fire in bursts of action potentials with short interspike intervals (2–10 msec). These high-frequency bursts may play a critical role in the functional behavior of hippocampal neurons, but synaptic plasticity at such short times has not been carefully studied. To study synaptic modulation at very short time intervals, we applied pairs of stimuli with interpulse intervals ranging from 7 to 50 msec to CA1 synapses isolated by the method of minimal stimulation in hippocampal slices. We have identified three components of short-term paired-pulse modulation, including (i) a form of synaptic depression manifested after a prior exocytotic event, (ii) a form of synaptic depression that does not depend on a prior exocytotic event and that we postulate is based on inactivation of presynaptic N-type Ca2+ channels, and (iii) a dependence of paired-pulse facilitation on the exocytotic history of the synapse.

Interactions between short-term and long-term plasticity: shooting for a moving target

Far from being static transmission units, synapses are highly dynamical elements that change over multiple time scales depending on the history of the neural activity of both the pre- and postsynaptic neuron. Moreover, synaptic changes on different time scales interact: long-term plasticity (LTP) can modify the properties of short-term plasticity (STP) in the same synapse. Most existing theories of synaptic plasticity focus on only one of these time scales (either STP or LTP or late-LTP) and the theoretical principles underlying their interactions are thus largely unknown. Here we develop a normative model of synaptic plasticity that combines both STP and LTP and predicts specific patterns for their interactions. Recently, it has been proposed that STP arranges for the local postsynaptic membrane potential at a synapse to behave as an optimal estimator of the presynaptic membrane potential based on the incoming spikes. Here we generalize this approach by considering an optimal estimator of a non-linear function of the membrane potential and the long-term synaptic efficacy—which itself may be subject to change on a slower time scale. We find that an increase in the long-term synaptic efficacy necessitates changes in the dynamics of STP. More precisely, for a realistic non-linear function to be estimated, our model predicts that after the induction of LTP, causing long-term synaptic efficacy to increase, a depressing synapse should become even more depressing. That is, in a protocol using trains of presynaptic stimuli, as the initial EPSP becomes stronger due to LTP, subsequent EPSPs should become weakened and this weakening should be more pronounced with LTP. This form of redistribution of synaptic efficacies agrees well with electrophysiological data on synapses connecting layer 5 pyramidal neurons.

Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity

GABAergic (GABA = γ-aminobutyric acid) neurons from different brain regions contain high levels of parvalbumin, both in their soma and in their neurites. Parvalbumin is a slow Ca2+ buffer that may affect the amplitude and time course of intracellular Ca2+ transients in terminals after an action potential, and hence may regulate short-term synaptic plasticity. To test this possibility, we have applied paired-pulse stimulations (with 30- to 300-ms intervals) at GABAergic synapses between interneurons and Purkinje cells, both in wild-type (PV+/+) mice and in parvalbumin knockout (PV−/−) mice. We observed paired-pulse depression in PV+/+ mice, but paired-pulse facilitation in PV−/− mice. In paired recordings of connected interneuron-Purkinje cells, dialysis of the presynaptic interneuron with the slow Ca2+ buffer EGTA (1 mM) rescues paired-pulse depression in PV−/− mice. These data show that parvalbumin potently modulates short-term synaptic plasticity.

Role of protein kinase C in short-term sensitization of {\it Aplysia}

Plasticity at the connections between sensory neurons and their follower cells in Aplysia has been used extensively as a model system to examine mechanisms of simple forms of learning, such as sensitization. Sensitization is induced, at least in part, by the transmitter serotonin (5-HT) and expressed in several forms, including facilitation of sensorimotor connections. Spike broadening has been believed to be a key mechanism underlying facilitation of nondepressed synapses. Previously, this broadening was believed to be dependent primarily on cAMP/protein kinase A (PKA)-mediated reduction of a noninactivating, relatively voltage-independent K$\sp{+}$ current termed the S-K$\sp+$ current (I$\sb{\rm K{,}S}$). Recent evidence, however, suggests that 5-HT-induced somatic spike broadening is composed of at least two components: a cAMP-dependent, rapidly developing component and a cAMP-independent, slowly developing component.^ Phorbol esters, activators of protein kinase C (PKC), mimicked the cAMP-independent component of 5-HT-induced broadening. Staurosporine, which inhibits PKC, had little effect on the rapidly developing component of 5-HT-induced broadening, but inhibited significantly the slowly developing component. These results suggest that PKC is involved in the cAMP-independent component of 5-HT-induced broadening. The membrane currents responsible for the slowly developing component of broadening were examined. Activation of PKC mimicked, and partially occluded, 5-HT-induced modulation of membrane currents above 0 mV, where a voltage-dependent K$\sp+$ current (I$\sb{\rm K{,}V}$) is significantly activated. This modulation was complex because it was associated with a reduction in the magnitude of I$\sb{\rm K{,}V}$, as well as a slowing of both activation and inactivation kinetics of I$\sb{\rm K{,}V}$. These results support the hypothesis that PKC modulates I$\sb{\rm K{,}V}$ and that this modulation contributes to the slowly developing component of 5-HT-induced broadening. Based on these results and others, a new scheme for 5-HT-induced spike broadening is proposed in which the modulatory effects are mediated via two second messenger/protein kinase systems converging and diverging on multiple ionic conductances.^ The relationship between spike broadening and synaptic facilitation was also examined. Pharmacological reduction of I$\sb{\rm K{,}V}$ by low concentrations of 4-aminopyridine (4-AP) led to spike broadening and facilitation of the nondepressed sensorimotor connections, indicating that spike broadening via the reduction of I$\sc{K,V}$ can facilitate the synaptic connection. Further analyses, however, revealed that 4-AP-induced facilitation has qualitative differences from 5-HT- and PKC-induced facilitation. These results suggest that 5-HT- and PKC-induced facilitation of nondepressed synapses is mediated, at least in part, by spike-duration independent (SDI) processes. Under certain conditions, the PKC inhibitor, staurosporine, significantly inhibited the 5-HT-induced facilitation of sensorimotor connections.^ Finally, it was found that activation of PKC increased a basal level of cAMP and that PKC caused desensitization of the 5-HT receptor, which may be a possible negative feedback mechanism through which an extracellular ligand, 5-HT, is regulated. These results suggest that these two second messenger/protein kinase pathways can interact in the sensory neuron. Thus, neuronal plasticity that may contribute to learning and memory appears to involve several complex and interactive processes. ^

Strong shift from HCO3- to CO2 uptake in Emiliania huxleyi with acidification: new approach unravels acclimation versus short-term pH effects

Effects of ocean acidification on Emiliania huxleyi strain RCC 1216 (calcifying, diploid life-cycle stage) and RCC 1217 (non-calcifying, haploid life-cycle stage) were investigated by measuring growth, elemental composition, and production rates under different pCO2 levels (380 and 950 µatm). In these differently acclimated cells, the photosynthetic carbon source was assessed by a (14)C disequilibrium assay, conducted over a range of ecologically relevant pH values (7.9-8.7). In agreement with previous studies, we observed decreased calcification and stimulated biomass production in diploid cells under high pCO2, but no CO2-dependent changes in biomass production for haploid cells. In both life-cycle stages, the relative contributions of CO2 and HCO3 (-) uptake depended strongly on the assay pH. At pH values =< 8.1, cells preferentially used CO2 (>= 90 % CO2), whereas at pH values >= 8.3, cells progressively increased the fraction of HCO3 (-) uptake (~45 % CO2 at pH 8.7 in diploid cells; ~55 % CO2 at pH 8.5 in haploid cells). In contrast to the short-term effect of the assay pH, the pCO2 acclimation history had no significant effect on the carbon uptake behavior. A numerical sensitivity study confirmed that the pH-modification in the (14)C disequilibrium method yields reliable results, provided that model parameters (e.g., pH, temperature) are kept within typical measurement uncertainties. Our results demonstrate a high plasticity of E. huxleyi to rapidly adjust carbon acquisition to the external carbon supply and/or pH, and provide an explanation for the paradoxical observation of high CO2 sensitivity despite the apparently high HCO3 (-) usage seen in previous studies.

Short-term Physiological Changes In Roots And Leaves Of Sugarcane Varieties Exposed To H2o2 In Root Medium.

The aim of this study was to evaluate the differential sensitivity of sugarcane genotypes to H2O2 in root medium. As a hypothesis, the drought tolerant genotype would be able to minimize the oxidative damage and maintain the water transport from roots to shoots, reducing the negative effects on photosynthesis. The sugarcane genotypes IACSP94-2094 (drought tolerant) and IACSP94-2101 (drought sensitive) were grown in a growth chamber and exposed to three levels of H2O2 in nutrient solution: control; 3mmolL(-1) and 80mmolL(-1). Leaf gas exchange, photochemical activity, root hydraulic conductance (Lr) and antioxidant metabolism in both roots and leaves were evaluated after 15min of treatment with H2O2. Although, root hydraulic conductance, stomatal aperture, apparent electron transport rate and instantaneous carboxylation efficiency have been reduced by H2O2 in both genotypes, IACSP94-2094 presented higher values of those variables as compared to IACSP94-2101. There was a significant genotypic variation in relation to the physiological responses of sugarcane to increasing H2O2 in root tissues, being root changes associated with modifications in plant shoots. IACSP94-2094 presented a root antioxidant system more effective against H2O2 in root medium, regardless H2O2 concentration. Under low H2O2 concentration, water transport and leaf gas exchange of IACSP94-2094 were less affected as compared to IACSP94-2101. Under high H2O2 concentration, the lower sensitivity of IACSP94-2094 was associated with increases in superoxide dismutase activity in roots and leaves and increases in catalase activity in roots. In conclusion, we propose a general model of sugarcane reaction to H2O2, linking root and shoot physiological responses.

Flicker perimetry in healthy subjects: influence of age and gender, learning effect and short-term fluctuation

PURPOSE: To determine the mean critical fusion frequency and the short-term fluctuation, to analyze the influence of age, gender, and the learning effect in healthy subjects undergoing flicker perimetry. METHODS: Study 1 - 95 healthy subjects underwent flicker perimetry once in one eye. Mean critical fusion frequency values were compared between genders, and the influence of age was evaluated using linear regression analysis. Study 2 - 20 healthy subjects underwent flicker perimetry 5 times in one eye. The first 3 sessions were separated by an interval of 1 to 30 days, whereas the last 3 sessions were performed within the same day. The first 3 sessions were used to investigate the presence of a learning effect, whereas the last 3 tests were used to calculate short-term fluctuation. RESULTS: Study 1 - Linear regression analysis demonstrated that mean global, foveal, central, and critical fusion frequency per quadrant significantly decreased with age (p<0.05).There were no statistically significant differences in mean critical fusion frequency values between males and females (p>0.05), with the exception of the central area and inferonasal quadrant (p=0.049 and p=0.011, respectively), where the values were lower in females. Study 2 - Mean global (p=0.014), central (p=0.008), and peripheral (p=0.03) critical fusion frequency were significantly lower in the first session compared to the second and third sessions. The mean global short-term fluctuation was 5.06±1.13 Hz, the mean interindividual and intraindividual variabilities were 11.2±2.8% and 6.4±1.5%, respectively. CONCLUSION: This study suggests that, in healthy subjects, critical fusion frequency decreases with age, that flicker perimetry is associated with a learning effect, and that a moderately high short-term fluctuation is expected.