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

Abstract

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 the 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 Mn²⁺, suggesting that it is a slowly accumulating Ca²⁺ current. We modify a mechanistic model of synaptic release by assuming that the low-voltage-activating Ca²⁺ 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 Ca²⁺ in response to multiple presynaptic voltage stimuli, which, in turn, results in synaptic facilitation. Additionally, we assume that proctolin increases the maximal conductances of Ca²⁺ 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.

Introduction

Neuromodulation can reconfigure a network to produce a multitude of outputs [9]. The crustacean stomatogastric nervous system (STNS) is one of the most extensively researched neural systems in studying the effects of neuromodulation. There are several reports of the actions of neuromodulators on intrinsic neuronal properties and synaptic strength in the STNS (see [10] for a review), yet there are few reports of neuromodulatory effects on the short-term dynamics of synaptic transmission. A recent report from our laboratory showed that neuromodulation could alter short-term synaptic dynamics to the extent that a depressing synapse can become facilitating [1]. Such a drastic shift in dynamics can have significant consequences for the role of that synapse in network activity. In this study, we use a combination of experiments and modeling to explore the synaptic mechanisms underlying the neuromodulator effects on the short-term dynamics of pyloric synapses.

We investigate the effects of the neuropeptide proctolin on the dynamics of the inhibitory synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron in the rhythmic pyloric network of the crab. This synapse has both spike-mediated and non-spike-mediated (graded) components and is the only chemical feedback to the pyloric pacemaker neurons. The graded component of this synapse demonstrates short-term depression in control saline, yet, in the presence of proctolin, low-amplitude (<30 mV) presynaptic stimulation causes the graded component of the LP to PD synapse to facilitate [1]. In contrast, with high-amplitude (>30 mV) stimuli, the synapse remains depressing in the presence of proctolin, albeit enhanced in strength. We show that the switch to facilitation is correlated with the activation of a slowly activating presynaptic inward current. This inward current is blocked by Mn²⁺, suggesting that it is a slowly accumulating Ca²⁺ current activated by proctolin.

We propose that the switch from depression to facilitation in the LP to PD synapse is due to modifications in presynaptic Ca²⁺ current kinetics. Ca²⁺ channels can be divided into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. LVA channels such as T-type Ca²⁺ currents begin to activate ∼−60 mV, peak at ∼−30 mV and their amplitude decreases with further depolarization [11]. Since LVA channels have a low activation threshold, they support action potential generation, regulate subthreshold oscillatory activities, produce graded transmission and modulate spike-mediated transmission [4]. HVA Ca²⁺ currents activate ∼−40 to −10 mV, peak at ∼0 mV [7], and are believed to underlie spike-mediated transmitter release [7].

LVA Ca²⁺ currents are usually inactivating. Many LVA Ca²⁺ currents consist of two kinetically distinct components: one that activates/inactivates rapidly (I_CaF), another that activates/inactivates slowly (I_CaS) [4], [5]. We propose that the LP neuron also has two LVA Ca²⁺ currents. Additionally, we predict that proctolin not only adjusts the amplitude of these two currents, but also causes I_CaS to activate even more slowly, which leads to accumulation of total Ca²⁺ current and facilitation of synaptic release from LP. Using a model of synaptic release, we demonstrate that these proposed effects of proctolin explain the switch in the LP to PD synapse from depression to facilitation, in response to low-amplitude presynaptic stimuli.