bioRxiv2021
Transmission between neurons in the extensive enteric neural networks of the gut involves synaptic potentials with vastly different time courses and underlying conductances. Most enteric neurons exhibit fast excitatory post-synaptic potentials (EPSPs) lasting 20-50 ms, but many also exhibit slow EPSPs that last up to 100 s. When large enough, slow EPSPs excite action potentials at the start of the slow depolarization, but how they affect action potentials evoked by fast EPSPs is unknown. Furthermore, two other sources of synaptic depolarization probably occur in enteric circuits, activated via GABAA or GABAC receptors; how these interact with other synaptic depolarizations is also unclear. We built a compartmental model of enteric neurons incorporating realistic voltage-dependent ion channels, then simulated fast EPSPs, slow EPSPs and GABAA or GABAC ligand-gated Cl- channels to explore these interactions. Model predictions were tested by imaging Ca2+ transients in myenteric neurons ex vivo as an indicator of their activity during synaptic interactions. The model could mimic firing of myenteric neurons in mouse colon evoked by depolarizing current during intracellular recording and the fast and slow EPSPs in these neurons. Subthreshold fast EPSPs evoked spikes during the rising phase of a slow EPSP, but suprathreshold fast EPSPs could not evoke spikes later in a slow EPSP. This predicted inhibition was confirmed by Ca2+ imaging in which stimuli that evoke slow EPSPs suppressed activity evoked by fast EPSPs in many myenteric neurons. The model also predicted that synchronous activation of GABAA receptors and fast EPSPs potentiated firing evoked by the latter, while synchronous activation of GABAC receptors with fast EPSPs, potentiated firing and then suppressed it. The results reveal that so-called slow EPSPs have a biphasic effect being likely to suppress fast EPSP evoked firing over very long periods, perhaps accounting for prolonged quiescent periods seen in enteric motor patterns. Author SummaryThe gastrointestinal tract is the only organ with an extensive semi-autonomous nervous system that generates complex contraction patterns independently. Communication between neurons in this "enteric" nervous system is via depolarizing synaptic events with dramatically different time courses including fast synaptic potentials lasting around 20-50 ms and slow depolarizing synaptic potentials lasting for 10 - 120 s. Most neurons have both. We explored how slow synaptic depolarizations affect generation of action potentials by fast synaptic potentials using computational simulation of small networks of neurons implemented as compartmental models with realistic membrane ion channels. We found that slow synaptic depolarizations have biphasic effects; they initially make fast synaptic potentials more likely to trigger action potentials, but then actually prevent action potential generation by fast synaptic potentials with the inhibition lasting several 10s of seconds. We confirmed the inhibitory effects of the slow synaptic depolarizations using live Ca imaging of enteric neurons from mouse colon in isolated tissue. Our results identify a novel form of synaptic inhibition in the enteric nervous system of the gut, which may account for the vastly differing time courses between signalling in individual gut neurons and rhythmic contractile patterns that often repeat at more than 60 s intervals.