Ionic current correlations underlie the global tuning of large numbers of neuronal activity attributes.

Ionic conductances in identified neurons are highly variable. This poses the crucial question of how such neurons can produce stable activity. Coexpression of ionic currents has been observed in an increasing number of neurons in different systems, suggesting that the coregulation of ionic channel expression, by thus linking their variability, may enable neurons to maintain relatively constant neuronal activity as suggested by a number of recent theoretical studies. We examine this hypothesis experimentally using the voltage- and dynamic-clamp techniques to first measure and then modify the ionic conductance levels of three currents in identified neurons of the crab pyloric network. We quantify activity by measuring 10 different attributes (oscillation period, spiking frequency, etc.), and find linear, positive and negative relationships between conductance pairs and triplets that can enable pyloric neurons to maintain activity attributes invariant. Consistent with experimental observations, some of the features most tightly regulated appear to be phase relationships of bursting activity. We conclude that covariation (and probably a tightly controlled coregulation) of ionic conductances can help neurons maintain certain attributes of neuronal activity invariant while at the same time allowing conductances to change over wide ranges in response to internal or environmental inputs and perturbations. Our results also show that neurons can tune neuronal activity globally via coordinate expression of ion currents.

Neuromodulatory changes in short-term synaptic dynamics may be mediated by two distinct mechanisms of presynaptic calcium entry.

Although synaptic output is known to be modulated by changes in presynaptic calcium channels, additional pathways for calcium entry into the presynaptic terminal, such as non-selective channels, could contribute to modulation of short term synaptic dynamics. We address this issue using computational modeling. The neuropeptide proctolin modulates the inhibitory synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron, two slow-wave bursting neurons in the pyloric network of the crab Cancer borealis. Proctolin enhances the strength of this synapse and also changes its dynamics. Whereas in control saline the synapse shows depression independent of the amplitude of the presynaptic LP signal, in proctolin, with high-amplitude presynaptic LP stimulation the synapse remains depressing while low-amplitude stimulation causes facilitation. We use simple calcium-dependent release models to explore two alternative mechanisms underlying these modulatory effects. In the first model, proctolin directly targets calcium channels by changing their activation kinetics which results in gradual accumulation of calcium with low-amplitude presynaptic stimulation, leading to facilitation. The second model uses the fact that proctolin is known to activate a non-specific cation current I ( MI ). In this model, we assume that the MI channels have some permeability to calcium, modeled to be a result of slow conformation change after binding calcium. This generates a gradual increase in calcium influx into the presynaptic terminals through the modulatory channel similar to that described in the first model. Each of these models can explain the modulation of the synapse by proctolin but with different consequences for network activity.

Peptide neuromodulation of synaptic dynamics in an oscillatory network.

Although neuromodulation of synapses is extensively documented, its consequences in the context of network oscillations are not well known. We examine the modulation of synaptic strength and short-term dynamics in the crab pyloric network by the neuropeptide proctolin. Pyloric oscillations are driven by a pacemaker group which receives feedback through the inhibitory synapse from the lateral pyloric (LP) to pyloric dilator (PD) neurons. We show that proctolin modulates the spike-mediated and graded components of the LP to PD synapse. Proctolin enhances the graded component and unmasks a surprising heterogeneity in its dynamics where there is depression or facilitation depending on the amplitude of the voltage waveform of the presynaptic LP neuron. The spike-mediated component is influenced by the baseline membrane potential and is also enhanced by proctolin at all baseline potentials. In addition to direct modulation of this synapse, proctolin also changes the shape and amplitude of the presynaptic voltage waveform which additionally enhances synaptic output during ongoing activity. During ongoing oscillations, proctolin reduces the variability of cycle period but only when the LP to PD synapse is functionally intact. Using the dynamic clamp technique we find that the reduction in variability is a direct consequence of modulation of the LP to PD synapse. These results demonstrate that neuromodulation of synapses involves complex and interacting influences that target different synaptic components and dynamics as well as the presynaptic voltage waveform. At the network level, modulation of feedback inhibition can result in reduction of variability and enhancement of stable oscillatory output.

Pacemaker neuron and network oscillations depend on a neuromodulator-regulated linear current.

Linear leak currents have been implicated in the regulation of neuronal excitability, generation of neuronal and network oscillations, and network state transitions. Yet, few studies have directly tested the dependence of network oscillations on leak currents or explored the role of leak currents on network activity. In the oscillatory pyloric network of decapod crustaceans neuromodulatory inputs are necessary for pacemaker activity. A large subset of neuromodulators is known to activate a single voltage-gated inward current I(MI), which has been shown to regulate the rhythmic activity of the network and its pacemaker neurons. Using the dynamic clamp technique, we show that the crucial component of I(MI) for the generation of oscillatory activity is only a close-to-linear portion of the current-voltage relationship. The nature of this conductance is such that the presence or the absence of neuromodulators effectively regulates the amount of leak current and the input resistance in the pacemaker neurons. When deprived of neuromodulatory inputs, pyloric oscillations are disrupted; yet, a linear reduction of the total conductance in a single neuron within the pacemaker group recovers not only the pacemaker activity in that neuron, but also leads to a recovery of oscillations in the entire pyloric network. The recovered activity produces proper frequency and phasing that is similar to that induced by neuromodulators. These results show that the passive properties of pacemaker neurons can significantly affect their capacity to generate and regulate the oscillatory activity of an entire network, and that this feature is exploited by neuromodulatory inputs.

Neuromodulation of short-term synaptic dynamics examined in a mechanistic model based on kinetics of calcium currents.

Network plasticity arises in large part due to the effects of exogenous neuromodulators. We investigate the neuromodulatory effects on short-term synaptic dynamics. The synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron in the pyloric network of the crab C. borealis has both spike-mediated and non-spike-mediated (graded) components. Previous studies have shown that the graded component of this synapse exhibits short-term depression. Recent results from our lab indicate that in the presence of neuromodulatory peptide proctolin, low-amplitude presynaptic stimuli switch the short-term dynamics of this graded component from depression to facilitation. In this study, we show that this facilitation is correlated with the activation of a presynaptic inward current that is blocked by Mn(2+) suggesting that it is a slowly-accumulating Ca(2+) current. We modify a mechanistic model of synaptic release by assuming that the low-voltage-activating Ca(2+) current in our system is composed of two currents with fast (I(CaF)) and slow (I(CaS)) kinetics. We show that if proctolin adjusts the activation rate of I(CaS), this leads to accumulation of local intracellular Ca(2+) in response to multiple presynaptic voltage stimuli which, in turn, results in synaptic facilitation. Additionally, we assume that proctolin increases the maximal conductances of Ca(2+) currents in the model, consistent with the increased synaptic release found in the experiments. We find that these two presynaptic actions of proctolin in the model are sufficient to describe its actions on the short-term dynamics of the LP to PD synapse.