A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract

Abstract

Intrinsic sensory neurons (ISNs) of the enteric nervous system respond to stimuli such as muscle tension, muscle length, distortion of the mucosa, and the chemical content in the lumen. ISNs form recurrent networks that probably drive many intestinal motor patterns and reflexes. ISNs express a large number of voltage- and calcium-gated ion channels, some of which are modified by inflammation or repeated physiological stimuli, but how interactions between different ionic currents in ISNs produce both normal and pathological behaviors in the intestine remains unclear. We constructed a model of ISNs including voltage-gated sodium and potassium channels, N-type calcium channels, big conductance calcium-dependent potassium (BK) channels, calcium-dependent nonspecific cation channels (NSCa), intermediate conductance calcium-dependent potassium (IK) channels, hyperpolarization-activated cation (Ih) channels, and internal calcium dynamics. The model was based on data from the literature and our electrophysiological studies. The model reproduced responses to short or long depolarizing current pulses and responses to long hyperpolarizing current pulses. Sensitivity analysis showed that Ih, IK, NSCa, and BK have the largest influence on the number of action potentials observed during prolonged depolarizations. The model also predicts that changes to the voltage of activation for Ih have a large influence on excitability, but changes to the time constant of activation for Ih have a minor effect. Our model identifies how interactions between different iconic currents influence the excitability of ISNs and highlights an important role for Ih in enteric neuroplasticity resulting from disease.

Cholera Toxin Induces Sustained Hyperexcitability in Myenteric, but Not Submucosal, AH Neurons in Guinea Pig Jejunum

“…The amplitude of the AHP ( p < 0.01, n = 17) and its duration ( p < 0.05, n = 15) were significantly reduced following CT treatment (amplitude: control 6.5 ± 0.8 mV, CT 3.9 ± 0.5 mV; duration: control: 15.5 ± 2.6 s, CT 8.5 ± 2.0 s) (Table 1). While the exact physiological function of the ADP has not been determined, our computational model predicts that an increase in ADP magnitude can increase the excitability of AH neurons in some ways (Chambers et al, 2014). Pursuant to this, we found a significant increase in ADP amplitude observed in CT-treated neurons compared to neurons in the control group ( p < 0.05, n = 17; control 8.5 ± 1.1 mV, CT 13 ± 1.3 mV) (Table 1).…”

“…The late AHP is critical in determining the excitability of AH neurons, since it has the capacity to limit both firing and slow excitatory transmission (Chambers et al, 2014). The amplitude of the AHP ( p < 0.01, n = 17) and its duration ( p < 0.05, n = 15) were significantly reduced following CT treatment (amplitude: control 6.5 ± 0.8 mV, CT 3.9 ± 0.5 mV; duration: control: 15.5 ± 2.6 s, CT 8.5 ± 2.0 s) (Table 1).…”

“…Myenteric AH neurons express a wide variety of different ion channels that contribute to their excitability (Chambers et al, 2014). For example, inflammation-induced increased excitability of these neurons is associated with an increase in an hyperpolarization-activated cyclic nucleotide dependent cation conductance ( I h ) , (Linden et al, 2003) whose activation reduces the amplitude and duration of the slow AHP in these neurons (Chambers et al, 2014).…”

“…For example, inflammation-induced increased excitability of these neurons is associated with an increase in an hyperpolarization-activated cyclic nucleotide dependent cation conductance ( I h ) , (Linden et al, 2003) whose activation reduces the amplitude and duration of the slow AHP in these neurons (Chambers et al, 2014). In contrast, CT does not cause inflammation or alter I h , but does reduce both the amplitude and duration of the AHP in myenteric AH neurons (Table 1).…”

“…The prolonged AHP is critical in determining the excitability of AH neurons, since it has the capacity to limit firing rate and slow excitatory transmission (Bertrand and Thomas, 2004). Other currents exhibited by AH neurons are also important for the regulation of cell excitability (Galligan et al, 1990; Rugiero et al, 2002; Nguyen et al, 2005; Chambers et al, 2014). There are also mechanosensitive myenteric neurons in guinea pig small intestine that lack the characteristics of AH neurons (for review see Schemann and Mazzuoli, 2010); in guinea pig colon, similar neurons appear to be S-type interneurons (Spencer and Smith, 2004), Whether they have sensory functions in small intestinal reflex pathways remains to be established.…”